STAT Transcription Factors in T Cell Control of Health and Disease

International Review of Cell and Molecular Biology

Volumn 331, Issue , 2017, Pages 123-180

  Goswami, R ^a   Kaplan, M H ^b  

^a AHMEDABAD UNIVERSITY   (India)

^b INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Autoimmunity; Immunodeficiency; Jak STAT molecules; T cells; Transcriptional regulation

Indexed keywords

CYTOKINE; JANUS KINASE; STAT PROTEIN; STAT1 PROTEIN; STAT3 PROTEIN; STAT4 PROTEIN; STAT5 PROTEIN; STAT6 PROTEIN;

ADAPTIVE IMMUNITY; ALLERGIC DISEASE; AUTOIMMUNE DISEASE; CELL MATURATION; CYTOTOXIC T LYMPHOCYTE; ENTERITIS; HELPER CELL; HUMAN; IMMUNE DEFICIENCY; IMMUNOREGULATION; INFLAMMATION; INNATE IMMUNITY; LYMPHOCYTE DIFFERENTIATION; PROTEIN EXPRESSION; REGULATORY T LYMPHOCYTE; SIGNAL TRANSDUCTION; T LYMPHOCYTE; TH1 CELL; TH17 CELL; TH2 CELL; TH9 CELL; ANIMAL; CYTOLOGY; DISEASES; GENETICS; HEALTH; METABOLISM; MUTATION;

ANIMALS; DISEASE; HEALTH; HUMANS; JANUS KINASES; MUTATION; STAT TRANSCRIPTION FACTORS; T-LYMPHOCYTES;

EID: 85020708816     PISSN: 19376448     EISSN: None     Source Type: Book Series    
DOI: 10.1016/bs.ircmb.2016.09.012     Document Type: Chapter

References (400)

1. Aaronson, D.S., Horvath, C.M., A road map for those who don't know JAK-STAT. Science 296 (2002), 1653–1655.
2. Aerts, N.E., Ebo, D.G., Bridts, C.H., Stevens, W.J., De Clerck, L.S., T cell signal transducer and activator of transcription (STAT) 4 and 6 are affected by adalimumab therapy in rheumatoid arthritis. Clin. Exp. Rheumatol. 28 (2010), 208–214.
3. Afkarian, M., Sedy, J.R., Yang, J., Jacobson, N.G., Cereb, N., Yang, S.Y., Murphy, T.L., Murphy, K.M., T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4 + T cells. Nat. Immunol. 3 (2002), 549–557.
4. Aittomaki, S., Pesu, M., Therapeutic targeting of the Jak/STAT pathway. Basic Clin. Pharmacol. Toxicol. 114 (2014), 18–23.
5. Akiba, H., Takeda, K., Kojima, Y., Usui, Y., Harada, N., Yamazaki, T., Ma, J., Tezuka, K., Yagita, H., Okumura, K., The role of ICOS in the CXCR5 + follicular B helper T cell maintenance in vivo. J. Immunol. 175 (2005), 2340–2348.
6. Ashino, S., Takeda, K., Li, H., Taylor, V., Joetham, A., Pine, P.R., Gelfand, E.W., Janus kinase 1/3 signaling pathways are key initiators of TH2 differentiation and lung allergic responses. J. Allergy Clin. Immunol. 133 (2014), 1162–1174.
7. Atreya, R., Mudter, J., Finotto, S., Mullberg, J., Jostock, T., Wirtz, S., Schutz, M., Bartsch, B., Holtmann, M., Becker, C., Strand, D., Czaja, J., Schlaak, J.F., Lehr, H.A., Autschbach, F., Schurmann, G., Nishimoto, N., Yoshizaki, K., Ito, H., Kishimoto, T., Galle, P.R., Rose-John, S., Neurath, M.F., Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo. Nat. Med. 6 (2000), 583–588.
8. Attridge, K., Wang, C.J., Wardzinski, L., Kenefeck, R., Chamberlain, J.L., Manzotti, C., Kopf, M., Walker, L.S., IL-21 inhibits T cell IL-2 production and impairs Treg homeostasis. Blood 119 (2012), 4656–4664.
9. Bachelez, H., Van De Kerkhof, P.C., Strohal, R., Kubanov, A., Valenzuela, F., Lee, J.H., Yakusevich, V., Chimenti, S., Papacharalambous, J., Proulx, J., Gupta, P., Tan, H., Tawadrous, M., Valdez, H., Wolk, R., Investigators, O.P.T.C., Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial. Lancet 386 (2015), 552–561.
10. Baecher-Allan, C., Viglietta, V., Hafler, D.A., Inhibition of human CD4(+)CD25(+ high) regulatory T cell function. J. Immunol. 169 (2002), 6210–6217.
11. Bandyopadhyay, S.K., De La Motte, C.A., Kessler, S.P., Hascall, V.C., Hill, D.R., Strong, S.A., Hyaluronan-mediated leukocyte adhesion and dextran sulfate sodium-induced colitis are attenuated in the absence of signal transducer and activator of transcription 1. Am. J. Pathol. 173 (2008), 1361–1368.
12. Barbulescu, K., Becker, C., Schlaak, J.F., Schmitt, E., Meyer Zum Buschenfelde, K.H., Neurath, M.F., IL-12 and IL-18 differentially regulate the transcriptional activity of the human IFN-gamma promoter in primary CD4 + T lymphocytes. J. Immunol. 160 (1998), 3642–3647.
13. Bartel, D.P., MicroRNAs: target recognition and regulatory functions. Cell 136 (2009), 215–233.
14. Bassil, R., Zhu, B., Lahoud, Y., Riella, L.V., Yagita, H., Elyaman, W., Khoury, S.J., Notch ligand delta-like 4 blockade alleviates experimental autoimmune encephalomyelitis by promoting regulatory T cell development. J. Immunol. 187 (2011), 2322–2328.
15. Bassil, R., Orent, W., Olah, M., Kurdi, A.T., Frangieh, M., Buttrick, T., Khoury, S.J., Elyaman, W., BCL6 controls Th9 cell development by repressing Il9 transcription. J. Immunol. 193 (2014), 198–207.
16. Battaglia, A., Buzzonetti, A., Baranello, C., Fanelli, M., Fossati, M., Catzola, V., Scambia, G., Fattorossi, A., Interleukin-21 (IL-21) synergizes with IL-2 to enhance T-cell receptor-induced human T-cell proliferation and counteracts IL-2/transforming growth factor-beta-induced regulatory T-cell development. Immunology 139 (2013), 109–120.
17. Baumann, C., Bonilla, W.V., Frohlich, A., Helmstetter, C., Peine, M., Hegazy, A.N., Pinschewer, D.D., Lohning, M., T-bet- and STAT4-dependent IL-33 receptor expression directly promotes antiviral Th1 cell responses. Proc. Natl. Acad. Sci. U.S.A. 112 (2015), 4056–4061.
18. Baumgart, D.C., Sandborn, W.J., Crohn's disease. Lancet 380 (2012), 1590–1605.
19. Bauquet, A.T., Jin, H., Paterson, A.M., Mitsdoerffer, M., Ho, I.C., Sharpe, A.H., Kuchroo, V.K., The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nat. Immunol. 10 (2009), 167–175.
20. Behera, A.K., Kumar, M., Lockey, R.F., Mohapatra, S.S., Adenovirus-mediated interferon gamma gene therapy for allergic asthma: involvement of interleukin 12 and STAT4 signaling. Hum. Gene Ther. 13 (2002), 1697–1709.
21. Bell, B.D., Kitajima, M., Larson, R.P., Stoklasek, T.A., Dang, K., Sakamoto, K., Wagner, K.-U., Kaplan, D.H., Reizis, B., Hennighausen, L., Ziegler, S.F., The transcription factor STAT5 is critical in dendritic cells for the development of TH2 but not TH1 responses. Nat. Immunol. 14 (2013), 364–371.
22. Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T.B., Oukka, M., Weiner, H.L., Kuchroo, V.K., Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441 (2006), 235–238.
23. Bi, C., Li, B., Cheng, Z., Hu, Y., Fang, Z., Zhai, A., Association study of STAT4 polymorphisms and type 1 diabetes in Northeastern Chinese Han population. Tissue Antigens 81 (2013), 137–140.
24. Blanco-Jerez, C., Plaza, J.F., Masjuan, J., Orensanz, L.M., Alvarez-Cermeno, J.C., Increased levels of IL-15 mRNA in relapsing—remitting multiple sclerosis attacks. J. Neuroimmunol. 128 (2002), 90–94.
25. Blease, K., Schuh, J.M., Jakubzick, C., Lukacs, N.W., Kunkel, S.L., Joshi, B.H., Puri, R.K., Kaplan, M.H., Hogaboam, C.M., Stat6-deficient mice develop airway hyperresponsiveness and peribronchial fibrosis during chronic fungal asthma. Am. J. Pathol. 160 (2002), 481–490.
26. Bossaller, L., Burger, J., Draeger, R., Grimbacher, B., Knoth, R., Plebani, A., Durandy, A., Baumann, U., Schlesier, M., Welcher, A.A., Peter, H.H., Warnatz, K., ICOS deficiency is associated with a severe reduction of CXCR5 + CD4 germinal center Th cells. J. Immunol. 177 (2006), 4927–4932.
27. Bot, A., Rodrigo, E., Wolfe, T., Bot, S., Von Herrath, M.G., Infection-triggered regulatory mechanisms override the role of STAT 4 in control of the immune response to influenza virus antigens. J. Virol. 77 (2003), 5794–5800.
28. Braunstein, J., Brutsaert, S., Olson, R., Schindler, C., STATs dimerize in the absence of phosphorylation. J. Biol. Chem. 278 (2003), 34133–34140.
29. Breitfeld, D., Ohl, L., Kremmer, E., Ellwart, J., Sallusto, F., Lipp, M., Forster, R., Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J. Exp. Med. 192 (2000), 1545–1552.
30. Brooks, A.J., Dai, W., O'Mara, M.L., Abankwa, D., Chhabra, Y., Pelekanos, R.A., Gardon, O., Tunny, K.A., Blucher, K.M., Morton, C.J., Parker, M.W., Sierecki, E., Gambin, Y., Gomez, G.A., Alexandrov, K., Wilson, I.A., Doxastakis, M., Mark, A.E., Waters, M.J., Mechanism of activation of protein kinase JAK2 by the growth hormone receptor. Science, 344, 2014, 1249783.
31. Bruns, H.A., Schindler, U., Kaplan, M.H., Expression of a constitutively active Stat6 in vivo alters lymphocyte homeostasis with distinct effects in T and B cells. J. Immunol. 170 (2003), 3478–3487.
32. Burchill, M.A., Yang, J., Vogtenhuber, C., Blazar, B.R., Farrar, M.A., IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3 + regulatory T cells. J. Immunol. 178 (2007), 280–290.
33. Carter, L.L., Murphy, K.M., Lineage-specific requirement for signal transducer and activator of transcription (Stat)4 in interferon gamma production from CD4(+) versus CD8(+) T cells. J. Exp. Med. 189 (1999), 1355–1360.
34. Casey, K.A., Mescher, M.F., IL-21 promotes differentiation of naive CD8 T cells to a unique effector phenotype. J. Immunol. 178 (2007), 7640–7648.
35. Chang, J.H., Kim, Y.J., Han, S.H., Kang, C.Y., IFN-gamma-STAT1 signal regulates the differentiation of inducible Treg: potential role for ROS-mediated apoptosis. Eur. J. Immunol. 39 (2009), 1241–1251.
36. Chang, H.C., Sehra, S., Goswami, R., Yao, W., Yu, Q., Stritesky, G.L., Jabeen, R., McKinley, C., Ahyi, A.N., Han, L., Nguyen, E.T., Robertson, M.J., Perumal, N.B., Tepper, R.S., Nutt, S.L., Kaplan, M.H., The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat. Immunol. 11 (2010), 527–534.
37. Chapgier, A., Wynn, R.F., Jouanguy, E., Filipe-Santos, O., Zhang, S., Feinberg, J., Hawkins, K., Casanova, J.L., Arkwright, P.D., Human complete Stat-1 deficiency is associated with defective type I and II IFN responses in vitro but immunity to some low virulence viruses in vivo. J. Immunol. 176 (2006), 5078–5083.
38. Chapgier, A., Kong, X.F., Boisson-Dupuis, S., Jouanguy, E., Averbuch, D., Feinberg, J., Zhang, S.Y., Bustamante, J., Vogt, G., Lejeune, J., Mayola, E., De Beaucoudrey, L., Abel, L., Engelhard, D., Casanova, J.L., A partial form of recessive STAT1 deficiency in humans. J. Clin. Invest. 119 (2009), 1502–1514.
39. Chapoval, S., Dasgupta, P., Dorsey, N.J., Keegan, A.D., Regulation of the T helper cell type 2 (Th2)/T regulatory cell (Treg) balance by IL-4 and STAT6. J. Leukoc. Biol. 87 (2010), 1011–1018.
40. Chapoval, S.P., Dasgupta, P., Smith, E.P., Detolla, L.J., Lipsky, M.M., Kelly-Welch, A.E., Keegan, A.D., STAT6 expression in multiple cell types mediates the cooperative development of allergic airway disease. J. Immunol. 186 (2011), 2571–2583.
41. Chen, H.W., Tsai, J.P., Yao, T.Y., Hsieh, C.L., Chen, I.H., Liu, S.J., TGF-beta and IL-21 cooperatively stimulate activated CD8(+) T cells to differentiate into Tc17 cells. Immunol. Lett. 174 (2016), 23–27.
42. Chiba, Y., Nakazawa, S., Todoroki, M., Shinozaki, K., Sakai, H., Misawa, M., Interleukin-13 augments bronchial smooth muscle contractility with an up-regulation of RhoA protein. Am. J. Respir. Cell Mol. Biol. 40 (2009), 159–167.
43. Chiba, Y., Todoroki, M., Nishida, Y., Tanabe, M., Misawa, M., A novel STAT6 inhibitor AS1517499 ameliorates antigen-induced bronchial hypercontractility in mice. Am. J. Respir. Cell Mol. Biol. 41 (2009), 516–524.
44. Chitnis, T., Najafian, N., Benou, C., Salama, A.D., Grusby, M.J., Sayegh, M.H., Khoury, S.J., Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis. J. Clin. Invest. 108 (2001), 739–747.
45. Choi, Y.S., Eto, D., Yang, J.A., Lao, C., Crotty, S., Cutting edge: STAT1 is required for IL-6-mediated Bcl6 induction for early follicular helper cell differentiation. J. Immunol. 190 (2013), 3049–3053.
46. Christophi, G.P., Rong, R., Holtzapple, P.G., Massa, P.T., Landas, S.K., Immune markers and differential signaling networks in ulcerative colitis and Crohn's disease. Inflamm. Bowel Dis. 18 (2012), 2342–2356.
47. Chtanova, T., Tangye, S.G., Newton, R., Frank, N., Hodge, M.R., Rolph, M.S., MacKay, C.R., T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells. J. Immunol. 173 (2004), 68–78.
48. Chua, K.H., Ng, J.G., Ng, C.C., Hilmi, I., Goh, K.L., Kee, B.P., Association of NOD1, CXCL16, STAT6 and TLR4 gene polymorphisms with Malaysian patients with Crohn's disease. PeerJ, 4, 2016, e1843.
49. Ciric, B., El-Behi, M., Cabrera, R., Zhang, G.X., Rostami, A., IL-23 drives pathogenic IL-17-producing CD8 + T cells. J. Immunol. 182 (2009), 5296–5305.
50. Coffman, R.L., Seymour, B.W., Hudak, S., Jackson, J., Rennick, D., Antibody to interleukin-5 inhibits helminth-induced eosinophilia in mice. Science 245 (1989), 308–310.
51. Connelly, T.M., Koltun, W.A., Berg, A.S., Hegarty, J.P., Brinton, D., Deiling, S., Poritz, L.S., Stewart, D.B., A single nucleotide polymorphism in the STAT5 gene favors colonic as opposed to small-bowel inflammation in Crohn's disease. Dis. Colon Rectum 56 (2013), 1068–1074.
52. Cooley, I.D., Read, K.A., Oestreich, K.J., Trans-presentation of IL-15 modulates STAT5 activation and Bcl-6 expression in TH1 cells. Sci. Rep., 5, 2015, 15722.
53. Costantino, G., Egerbacher, M., Kolbe, T., Karaghiosoff, M., Strobl, B., Vogl, C., Helmreich, M., Muller, M., Tyk2 and signal transducer and activator of transcription 1 contribute to intestinal I/R injury. Shock 29 (2008), 238–244.
54. Cote-Sierra, J., Foucras, G., Guo, L., Chiodetti, L., Young, H.A., Hu-Li, J., Zhu, J., Paul, W.E., Interleukin 2 plays a central role in Th2 differentiation. Proc. Natl. Acad. Sci. U.S.A. 101 (2004), 3880–3885.
55. Croft, M., Carter, L., Swain, S.L., Dutton, R.W., Generation of polarized antigen-specific CD8 effector populations: reciprocal action of interleukin (IL)-4 and IL-12 in promoting type 2 versus type 1 cytokine profiles. J. Exp. Med. 180 (1994), 1715–1728.
56. Crotty, S., Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 29 (2011), 621–663.
57. Cua, D.J., Sherlock, J., Chen, Y., Murphy, C.A., Joyce, B., Seymour, B., Lucian, L., To, W., Kwan, S., Churakova, T., Zurawski, S., Wiekowski, M., Lira, S.A., Gorman, D., Kastelein, R.A., Sedgwick, J.D., Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421 (2003), 744–748.
58. Dardalhon, V., Awasthi, A., Kwon, H., Galileos, G., Gao, W., Sobel, R.A., Mitsdoerffer, M., Strom, T.B., Elyaman, W., Ho, I.C., Khoury, S., Oukka, M., Kuchroo, V.K., IL-4 inhibits TGF-beta-induced Foxp3 + T cells, and together with TGF-beta, generates IL-9 + IL-10 + Foxp3(-) effector T cells. Nat. Immunol. 9 (2008), 1347–1355.
59. Darnell, J.E. Jr., STATs and gene regulation. Science 277 (1997), 1630–1635.
60. Davidson, T.S., Dipaolo, R.J., Andersson, J., Shevach, E.M., Cutting Edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3 + T regulatory cells. J. Immunol. 178 (2007), 4022–4026.
61. D'Cruz, L.M., Klein, L., Development and function of agonist-induced CD25 + Foxp3 + regulatory T cells in the absence of interleukin 2 signaling. Nat. Immunol. 6 (2005), 1152–1159.
62. De Prati, A.C., Ciampa, A.R., Cavalieri, E., Zaffini, R., Darra, E., Menegazzi, M., Suzuki, H., Mariotto, S., STAT1 as a new molecular target of anti-inflammatory treatment. Curr. Med. Chem. 12 (2005), 1819–1828.
63. Dembic, Z., Beginning of the end of (understanding) the immune response. Scand. J. Immunol. 68 (2008), 381–382.
64. Diaz-Gallo, L.M., Palomino-Morales, R.J., Gomez-Garcia, M., Cardena, C., Rodrigo, L., Nieto, A., Alcain, G., Cueto, I., Lopez-Nevot, M.A., Martin, J., STAT4 gene influences genetic predisposition to ulcerative colitis but not Crohn's disease in the Spanish population: a replication study. Hum. Immunol. 71 (2010), 515–519.
65. Dipaolo, R.J., Brinster, C., Davidson, T.S., Andersson, J., Glass, D., Shevach, E.M., Autoantigen-specific TGFbeta-induced Foxp3 + regulatory T cells prevent autoimmunity by inhibiting dendritic cells from activating autoreactive T cells. J. Immunol. 179 (2007), 4685–4693.
66. Domeier, P.P., Chodisetti, S.B., Soni, C., Schell, S.L., Elias, M.J., Wong, E.B., Cooper, T.K., Kitamura, D., Rahman, Z.S., IFN-gamma receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity. J. Exp. Med. 213 (2016), 715–732.
67. Dong, J., Wang, Q.X., Zhou, C.Y., Ma, X.F., Zhang, Y.C., Activation of the STAT1 signalling pathway in lupus nephritis in MRL/lpr mice. Lupus 16 (2007), 101–109.
68. Dorsey, N.J., Chapoval, S.P., Smith, E.P., Skupsky, J., Scott, D.W., Keegan, A.D., STAT6 controls the number of regulatory T cells in vivo, thereby regulating allergic lung inflammation. J. Immunol. 191 (2013), 1517–1528.
69. Drachman, J.G., Millett, K.M., Kaushansky, K., Thrombopoietin signal transduction requires functional JAK2, not TYK2. J. Biol. Chem. 274 (1999), 13480–13484.
70. Duhen, R., Glatigny, S., Arbelaez, C.A., Blair, T.C., Oukka, M., Bettelli, E., Cutting edge: the pathogenicity of IFN-gamma-producing Th17 cells is independent of T-bet. J. Immunol. 190 (2013), 4478–4482.
71. Dupuis, S., Jouanguy, E., Al-Hajjar, S., Fieschi, C., Al-Mohsen, I.Z., Al-Jumaah, S., Yang, K., Chapgier, A., Eidenschenk, C., Eid, P., Al Ghonaium, A., Tufenkeji, H., Frayha, H., Al-Gazlan, S., AL-Rayes, H., Schreiber, R.D., Gresser, I., Casanova, J.L., Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency. Nat. Genet. 33 (2003), 388–391.
72. Eddahri, F., Denanglaire, S., Bureau, F., Spolski, R., Leonard, W.J., Leo, O., Andris, F., Interleukin-6/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities. Blood 113 (2009), 2426–2433.
73. El-Behi, M., Dai, H., Magalhaes, J.G., Hwang, D., Zhang, G.X., Rostami, A., Ciric, B., Committed Tc17 cells are phenotypically and functionally resistant to the effects of IL-27. Eur. J. Immunol. 44 (2014), 3003–3014.
74. Else, K.J., Finkelman, F.D., Maliszewski, C.R., Grencis, R.K., Cytokine-mediated regulation of chronic intestinal helminth infection. J. Exp. Med. 179 (1994), 347–351.
75. Elyaman, W., Bradshaw, E.M., Uyttenhove, C., Dardalhon, V., Awasthi, A., Imitola, J., Bettelli, E., Oukka, M., Van Snick, J., Renauld, J.C., Kuchroo, V.K., Khoury, S.J., IL-9 induces differentiation of TH17 cells and enhances function of FoxP3 + natural regulatory T cells. Proc. Natl. Acad. Sci. U.S.A. 106 (2009), 12885–12890.
76. Eto, D., Lao, C., Ditoro, D., Barnett, B., Escobar, T.C., Kageyama, R., Yusuf, I., Crotty, S., IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation. PLoS One, 6, 2011, e17739.
77. Fieschi, C., Dupuis, S., Catherinot, E., Feinberg, J., Bustamante, J., Breiman, A., Altare, F., Baretto, R., Le Deist, F., Kayal, S., Koch, H., Richter, D., Brezina, M., Aksu, G., Wood, P., Al-Jumaah, S., Raspall, M., Da Silva Duarte, A.J., Tuerlinckx, D., Virelizier, J.L., Fischer, A., Enright, A., Bernhoft, J., Cleary, A.M., Vermylen, C., Rodriguez-Gallego, C., Davies, G., Blutters-Sawatzki, R., Siegrist, C.A., Ehlayel, M.S., Novelli, V., Haas, W.H., Levy, J., Freihorst, J., Al-Hajjar, S., Nadal, D., DE Moraes Vasconcelos, D., Jeppsson, O., Kutukculer, N., Frecerova, K., Caragol, I., Lammas, D., Kumararatne, D.S., Abel, L., Casanova, J.L., Low penetrance, broad resistance, and favorable outcome of interleukin 12 receptor beta1 deficiency: medical and immunological implications. J. Exp. Med. 197 (2003), 527–535.
78. Finkelman, F.D., Morris, S.C., Orekhova, T., Mori, M., Donaldson, D., Reiner, S.L., Reilly, N.L., Schopf, L., Urban, J.F. Jr., Stat6 regulation of in vivo IL-4 responses. J. Immunol. 164 (2000), 2303–2310.
79. Flanagan, S.E., Haapaniemi, E., Russell, M.A., Caswell, R., Lango Allen, H., De Franco, E., McDonald, T.J., Rajala, H., Ramelius, A., Barton, J., Heiskanen, K., Heiskanen-Kosma, T., Kajosaari, M., Murphy, N.P., Milenkovic, T., Seppanen, M., Lernmark, A., Mustjoki, S., Otonkoski, T., Kere, J., Morgan, N.G., Ellard, S., Hattersley, A.T., Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nat. Genet. 46 (2014), 812–814.
80. Fleischmann, R., Kremer, J., Cush, J., Schulze-Koops, H., Connell, C.A., Bradley, J.D., Gruben, D., Wallenstein, G.V., Zwillich, S.H., Kanik, K.S., Investigators, O.S., Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N. Engl. J. Med. 367 (2012), 495–507.
81. Forbes, E.E., Groschwitz, K., Abonia, J.P., Brandt, E.B., Cohen, E., Blanchard, C., Ahrens, R., Seidu, L., McKenzie, A., Strait, R., Finkelman, F.D., Foster, P.S., Matthaei, K.I., Rothenberg, M.E., Hogan, S.P., IL-9- and mast cell-mediated intestinal permeability predisposes to oral antigen hypersensitivity. J. Exp. Med. 205 (2008), 897–913.
82. Foster, P.S., Webb, D.C., Yang, M., Herbert, C., Kumar, R.K., Dissociation of T helper type 2 cytokine-dependent airway lesions from signal transducer and activator of transcription 6 signalling in experimental chronic asthma. Clin. Exp. Allergy 33 (2003), 688–695.
83. Fridman, J.S., Scherle, P.A., Collins, R., Burn, T., Neilan, C.L., Hertel, D., Contel, N., Haley, P., Thomas, B., Shi, J., Collier, P., Rodgers, J.D., Shepard, S., Metcalf, B., Hollis, G., Newton, R.C., Yeleswaram, S., Friedman, S.M., Vaddi, K., Preclinical evaluation of local JAK1 and JAK2 inhibition in cutaneous inflammation. J. Invest. Dermatol. 131 (2011), 1838–1844.
84. Frisullo, G., Angelucci, F., Caggiula, M., Nociti, V., Iorio, R., Patanella, A.K., Sancricca, C., Mirabella, M., Tonali, P.A., Batocchi, A.P., pSTAT1, pSTAT3, and T-bet expression in peripheral blood mononuclear cells from relapsing-remitting multiple sclerosis patients correlates with disease activity. J. Neurosci. Res. 84 (2006), 1027–1036.
85. Fu, Y.X., Chaplin, D.D., Development and maturation of secondary lymphoid tissues. Annu. Rev. Immunol. 17 (1999), 399–433.
86. Fulkerson, P.C., Zimmermann, N., Hassman, L.M., Finkelman, F.D., Rothenberg, M.E., Pulmonary chemokine expression is coordinately regulated by STAT1, STAT6, and IFN-gamma. J. Immunol. 173 (2004), 7565–7574.
87. Furtado, G.C., Curotto de Lafaille, M.A., Kutchukhidze, N., Lafaille, J.J., Interleukin 2 signaling is required for CD4(+) regulatory T cell function. J. Exp. Med. 196 (2002), 851–857.
88. Genovese, M.C., Kremer, J., Zamani, O., Ludivico, C., Krogulec, M., Xie, L., Beattie, S.D., Koch, A.E., Cardillo, T.E., Rooney, T.P., Macias, W.L., De Bono, S., Schlichting, D.E., Smolen, J.S., Baricitinib in patients with refractory rheumatoid arthritis. N. Engl. J. Med. 374 (2016), 1243–1252.
89. Gerlach, C., Van Heijst, J.W., Swart, E., Sie, D., Armstrong, N., Kerkhoven, R.M., Zehn, D., Bevan, M.J., Schepers, K., Schumacher, T.N., One naive T cell, multiple fates in CD8 + T cell differentiation. J. Exp. Med. 207 (2010), 1235–1246.
90. Gernez, Y., Tirouvanziam, R., Nguyen, K.D., Herzenberg, L.A., Krensky, A.M., Nadeau, K.C., Altered phosphorylated signal transducer and activator of transcription profile of CD4 + CD161 + T cells in asthma: modulation by allergic status and oral corticosteroids. J. Allergy Clin. Immunol. 120 (2007), 1441–1448.
91. Ghoreschi, K., Laurence, A., O'Shea, J.J., Janus kinases in immune cell signaling. Immunol. Rev. 228 (2009), 273–287.
92. Ghoreschi, K., Laurence, A., Yang, X.P., Tato, C.M., Mcgeachy, M.J., Konkel, J.E., Ramos, H.L., Wei, L., Davidson, T.S., Bouladoux, N., Grainger, J.R., Chen, Q., Kanno, Y., Watford, W.T., Sun, H.W., Eberl, G., Shevach, E.M., Belkaid, Y., Cua, D.J., Chen, W., O'Shea, J.J., Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 467 (2010), 967–971.
93. Ghoreschi, K., Jesson, M.I., Li, X., Lee, J.L., Ghosh, S., Alsup, J.W., Warner, J.D., Tanaka, M., Steward-Tharp, S.M., Gadina, M., Thomas, C.J., Minnerly, J.C., Storer, C.E., Labranche, T.P., Radi, Z.A., Dowty, M.E., Head, R.D., Meyer, D.M., Kishore, N., O'shea, J.J., Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J. Immunol. 186 (2011), 4234–4243.
94. Gigoux, M., Shang, J., Pak, Y., Xu, M., Choe, J., Mak, T.W., Suh, W.K., Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase. Proc. Natl. Acad. Sci. U.S.A. 106 (2009), 20371–20376.
95. Gil, M.P., Salomon, R., Louten, J., Biron, C.A., Modulation of STAT1 protein levels: a mechanism shaping CD8 T-cell responses in vivo. Blood 107 (2006), 987–993.
96. Glas, J., Seiderer, J., Nagy, M., Fries, C., Beigel, F., Weidinger, M., Pfennig, S., Klein, W., Epplen, J.T., Lohse, P., Folwaczny, M., Goke, B., Ochsenkuhn, T., Diegelmann, J., Muller-Myhsok, B., Roeske, D., Brand, S., Evidence for STAT4 as a common autoimmune gene: rs7574865 is associated with colonic Crohn's disease and early disease onset. PLoS One, 5, 2010, e10373.
97. Glosson, N.L., Bruns, H.A., Kaplan, M.H., Wheezing and itching: the requirement for STAT proteins in allergic inflammation. JAKSTAT 1 (2012), 3–12.
98. Glosson-Byers, N.L., Sehra, S., Kaplan, M.H., STAT4 is required for IL-23 responsiveness in Th17 memory cells and NKT cells. JAKSTAT, 3, 2014, e955393.
99. Gomez-Rodriguez, J., Meylan, F., Handon, R., Hayes, E.T., Anderson, S.M., Kirby, M.R., Siegel, R.M., Schwartzberg, P.L., Itk is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4. Nat. Commun., 7, 2016, 10857.
100. Good-Jacobson, K.L., Szumilas, C.G., Chen, L., Sharpe, A.H., Tomayko, M.M., Shlomchik, M.J., PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells. Nat. Immunol. 11 (2010), 535–542.
101. Goodman, W.A., Levine, A.D., Massari, J.V., Sugiyama, H., McCormick, T.S., Cooper, K.D., IL-6 signaling in psoriasis prevents immune suppression by regulatory T cells. J. Immunol. 183 (2009), 3170–3176.
102. Gordon, R.A., Grigoriev, G., Lee, A., Kalliolias, G.D., Ivashkiv, L.B., The interferon signature and STAT1 expression in rheumatoid arthritis synovial fluid macrophages are induced by tumor necrosis factor alpha and counter-regulated by the synovial fluid microenvironment. Arthritis Rheum. 64 (2012), 3119–3128.
103. Goswami, R., Jabeen, R., Yagi, R., Pham, D., Zhu, J., Goenka, S., Kaplan, M.H., STAT6-dependent regulation of Th9 development. J. Immunol. 188 (2012), 968–975.
104. Grange, M., Verdeil, G., Arnoux, F., Griffon, A., Spicuglia, S., Maurizio, J., Buferne, M., Schmitt-Verhulst, A.M., Auphan-Anezin, N., Active STAT5 regulates T-bet and eomesodermin expression in CD8 T cells and imprints a T-bet-dependent Tc1 program with repressed IL-6/TGF-beta1 signaling. J. Immunol. 191 (2013), 3712–3724.
105. Hald, A., Andres, R.M., Salskov-Iversen, M.L., Kjellerup, R.B., Iversen, L., Johansen, C., STAT1 expression and activation is increased in lesional psoriatic skin. Br. J. Dermatol. 168 (2013), 302–310.
106. Hamada, H., Garcia-Hernandez, M.D.E.L., Reome, J.B., Misra, S.K., Strutt, T.M., Mckinstry, K.K., Cooper, A.M., Swain, S.L., Dutton, R.W., Tc17, a unique subset of CD8 T cells that can protect against lethal influenza challenge. J. Immunol. 182 (2009), 3469–3481.
107. Hambleton, S., Goodbourn, S., Young, D.F., Dickinson, P., Mohamad, S.M., Valappil, M., Mcgovern, N., Cant, A.J., Hackett, S.J., Ghazal, P., Morgan, N.V., Randall, R.E., STAT2 deficiency and susceptibility to viral illness in humans. Proc. Natl. Acad. Sci. U.S.A. 110 (2013), 3053–3058.
108. Hamel, K.M., Cao, Y., Wang, Y., Rodeghero, R., Kobezda, T., Chen, L., Finnegan, A., B7-H1 expression on non-B and non-T cells promotes distinct effects on T- and B-cell responses in autoimmune arthritis. Eur. J. Immunol. 40 (2010), 3117–3127.
109. Hamilton, J.A., Colony-stimulating factors in inflammation and autoimmunity. Nat. Rev. Immunol. 8 (2008), 533–544.
110. Hams, E., Mccarron, M.J., Amu, S., Yagita, H., Azuma, M., Chen, L., Fallon, P.G., Blockade of B7-H1 (programmed death ligand 1) enhances humoral immunity by positively regulating the generation of T follicular helper cells. J. Immunol. 186 (2011), 5648–5655.
111. Han, X., Osuntokun, B., Benight, N., Loesch, K., Frank, S.J., Denson, L.A., Signal transducer and activator of transcription 5b promotes mucosal tolerance in pediatric Crohn's disease and murine colitis. Am. J. Pathol. 169 (2006), 1999–2013.
112. Han, X., Ren, X., Jurickova, I., Groschwitz, K., Pasternak, B.A., Xu, H., Wilson, T.A., Hogan, S.P., Denson, L.A., Regulation of intestinal barrier function by signal transducer and activator of transcription 5b. Gut 58 (2009), 49–58.
113. Happel, K.I., Dubin, P.J., Zheng, M., Ghilardi, N., Lockhart, C., Quinton, L.J., Odden, A.R., Shellito, J.E., Bagby, G.J., Nelson, S., Kolls, J.K., Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae. J. Exp. Med. 202 (2005), 761–769.
114. Harada, T., Kyttaris, V., Li, Y., Juang, Y.T., Wang, Y., Tsokos, G.C., Increased expression of STAT3 in SLE T cells contributes to enhanced chemokine-mediated cell migration. Autoimmunity 40 (2007), 1–8.
115. Harris, T.J., Grosso, J.F., Yen, H.R., Xin, H., Kortylewski, M., Albesiano, E., Hipkiss, E.L., Getnet, D., Goldberg, M.V., Maris, C.H., Housseau, F., Yu, H., Pardoll, D.M., Drake, C.G., Cutting edge: an in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity. J. Immunol. 179 (2007), 4313–4317.
116. Hedrich, C.M., Rauen, T., Apostolidis, S.A., Grammatikos, A.P., Rodriguez Rodriguez, N., Ioannidis, C., Kyttaris, V.C., Crispin, J.C., Tsokos, G.C., Stat3 promotes IL-10 expression in lupus T cells through trans-activation and chromatin remodeling. Proc. Natl. Acad. Sci. U.S.A. 111 (2014), 13457–13462.
117. Henkels, K.M., Frondorf, K., Gonzalez-Mejia, M.E., Doseff, A.L., Gomez-Cambronero, J., IL-8-induced neutrophil chemotaxis is mediated by Janus kinase 3 (JAK3). FEBS Lett. 585 (2011), 159–166.
118. Hershey, G.K., Friedrich, M.F., Esswein, L.A., Thomas, M.L., Chatila, T.A., The association of atopy with a gain-of-function mutation in the alpha subunit of the interleukin-4 receptor. N. Engl. J. Med. 337 (1997), 1720–1725.
119. Hofmann, S.R., Lam, A.Q., Frank, S., Zhou, Y.J., Ramos, H.L., Kanno, Y., Agnello, D., Youle, R.J., O'Shea, J.J., Jak3-independent trafficking of the common gamma chain receptor subunit: chaperone function of Jaks revisited. Mol. Cell. Biol. 24 (2004), 5039–5049.
120. Holz, A., Bot, A., Coon, B., Wolfe, T., Grusby, M.J., Von Herrath, M.G., Disruption of the STAT4 signaling pathway protects from autoimmune diabetes while retaining antiviral immune competence. J. Immunol. 163 (1999), 5374–5382.
121. Hoshino, A., Tsuji, T., Matsuzaki, J., Jinushi, T., Ashino, S., Teramura, T., Chamoto, K., Tanaka, Y., Asakura, Y., Sakurai, T., Mita, Y., Takaoka, A., Nakaike, S., Takeshima, T., Ikeda, H., Nishimura, T., STAT6-mediated signaling in Th2-dependent allergic asthma: critical role for the development of eosinophilia, airway hyper-responsiveness and mucus hypersecretion, distinct from its role in Th2 differentiation. Int. Immunol. 16 (2004), 1497–1505.
122. Hsieh, C.S., Macatonia, S.E., Tripp, C.S., Wolf, S.F., O'Garra, A., Murphy, K.M., Development of TH1 CD4 + T cells through IL-12 produced by Listeria-induced macrophages. Science 260 (1993), 547–549.
123. Huang, W., Na, L., Fidel, P.L., Schwarzenberger, P., Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. J. Infect. Dis. 190 (2004), 624–631.
124. Huber, M., Heink, S., Grothe, H., Guralnik, A., Reinhard, K., Elflein, K., Hunig, T., Mittrucker, H.W., Brustle, A., Kamradt, T., Lohoff, M., A Th17-like developmental process leads to CD8(+) Tc17 cells with reduced cytotoxic activity. Eur. J. Immunol. 39 (2009), 1716–1725.
125. Hwa, V., Nadeau, K., Wit, J.M., Rosenfeld, R.G., STAT5b deficiency: lessons from STAT5b gene mutations. Best Pract. Res. Clin. Endocrinol. Metab. 25 (2011), 61–75.
126. International Multiple Sclerosis Genetics Consortium, Beecham, A.H., Patsopoulos, N.A., Xifara, D.K., Davis, M.F., Kemppinen, A., Cotsapas, C., Shah, T.S., Spencer, C., Booth, D., Goris, A., Oturai, A., Saarela, J., Fontaine, B., Hemmer, B., Martin, C., Zipp, F., D'Alfonso, S., Martinelli-Boneschi, F., Taylor, B., Harbo, H.F., Kockum, I., Hillert, J., Olsson, T., Ban, M., Oksenberg, J.R., Hintzen, R., Barcellos, L.F., Wellcome Trust Case Control Consortium 2, International IBD Genetic Consortium, Agliardi, C., Alfredsson, L., Alizadeh, M., Anderson, C., Andrews, R., Sondergaard, H.B., Baker, A., Band, G., Baranzini, S.E., Barizzone, N., Barrett, J., Bellenguez, C., Bergamaschi, L., Bernardinelli, L., Berthele, A., Biberacher, V., Binder, T.M., Blackburn, H., Bomfim, I.L., Brambilla, P., Broadley, S., Brochet, B., Brundin, L., Buck, D., Butzkueven, H., Caillier, S.J., Camu, W., Carpentier, W., Cavalla, P., Celius, E.G., Coman, I., Comi, G., Corrado, L., Cosemans, L., Cournu-Rebeix, I., Cree, B.A., Cusi, D., Damotte, V., Defer, G., Delgado, S.R., Deloukas, P., Di Sapio, A., Dilthey, A.T., Donnelly, P., Dubois, B., Duddy, M., Edkins, S., Elovaara, I., Esposito, F., Evangelou, N., Fiddes, B., Field, J., Franke, A., Freeman, C., Frohlich, I.Y., Galimberti, D., Gieger, C., Gourraud, P.A., Graetz, C., Graham, A., Grummel, V., Guaschino, C., Hadjixenofontos, A., Hakonarson, H., Halfpenny, C., Hall, G., Hall, P., Hamsten, A., Harley, J., Harrower, T., et al. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat. Genet. 45 (2013), 1353–1360.
127. Jabeen, R., Miller, L., Yao, W., Gupta, S., Steiner, S., Kaplan, M.H., Altered STAT4 isoform expression in patients with inflammatory bowel disease. Inflamm. Bowel Dis. 21 (2015), 2383–2392.
128. Jager, A., Dardalhon, V., Sobel, R.A., Bettelli, E., Kuchroo, V.K., Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J. Immunol. 183 (2009), 7169–7177.
129. Jankovic, D., Kullberg, M.C., Noben-Trauth, N., Caspar, P., Paul, W.E., Sher, A., Single cell analysis reveals that IL-4 receptor/Stat6 signaling is not required for the in vivo or in vitro development of CD4 + lymphocytes with a Th2 cytokine profile. J. Immunol. 164 (2000), 3047–3055.
130. Jee, Y., Kim, G., Tanuma, N., Matsumoto, Y., STAT expression and localization in the central nervous system during autoimmune encephalomyelitis in Lewis rats. J. Neuroimmunol. 114 (2001), 40–47.
131. Johnston, R.J., Choi, Y.S., Diamond, J.A., Yang, J.A., Crotty, S., STAT5 is a potent negative regulator of TFH cell differentiation. J. Exp. Med. 209 (2012), 243–250.
132. Jostins, L., Ripke, S., Weersma, R.K., Duerr, R.H., Mcgovern, D.P., Hui, K.Y., Lee, J.C., Schumm, L.P., Sharma, Y., Anderson, C.A., Essers, J., Mitrovic, M., Ning, K., Cleynen, I., Theatre, E., Spain, S.L., Raychaudhuri, S., Goyette, P., Wei, Z., Abraham, C., Achkar, J.P., Ahmad, T., Amininejad, L., Ananthakrishnan, A.N., Andersen, V., Andrews, J.M., Baidoo, L., Balschun, T., Bampton, P.A., Bitton, A., Boucher, G., Brand, S., Buning, C., Cohain, A., Cichon, S., D'Amato, M., De Jong, D., Devaney, K.L., Dubinsky, M., Edwards, C., Ellinghaus, D., Ferguson, L.R., Franchimont, D., Fransen, K., Gearry, R., Georges, M., Gieger, C., Glas, J., Haritunians, T., Hart, A., Hawkey, C., Hedl, M., Hu, X., Karlsen, T.H., Kupcinskas, L., Kugathasan, S., Latiano, A., Laukens, D., Lawrance, I.C., Lees, C.W., Louis, E., Mahy, G., Mansfield, J., Morgan, A.R., Mowat, C., Newman, W., Palmieri, O., Ponsioen, C.Y., Potocnik, U., Prescott, N.J., Regueiro, M., Rotter, J.I., Russell, R.K., Sanderson, J.D., Sans, M., Satsangi, J., Schreiber, S., Simms, L.A., Sventoraityte, J., Targan, S.R., Taylor, K.D., Tremelling, M., Verspaget, H.W., De Vos, M., Wijmenga, C., Wilson, D.C., Winkelmann, J., Xavier, R.J., Zeissig, S., Zhang, B., Zhang, C.K., Zhao, H., International IBD Genetics Consortium, Silverberg, M.S., Annese, V., Hakonarson, H., Brant, S.R., Radford-Smith, G., Mathew, C.G., Rioux, J.D., et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491 (2012), 119–124.
133. Kaech, S.M., Cui, W., Transcriptional control of effector and memory CD8 + T cell differentiation. Nat. Rev. Immunol. 12 (2012), 749–761.
134. Kagami, S., Nakajima, H., Suto, A., Hirose, K., Suzuki, K., Morita, S., Kato, I., Saito, Y., Kitamura, T., Iwamoto, I., Stat5a regulates T helper cell differentiation by several distinct mechanisms. Blood 97 (2001), 2358–2365.
135. Kalia, V., Sarkar, S., Subramaniam, S., Haining, W.N., Smith, K.A., Ahmed, R., Prolonged interleukin-2Ralpha expression on virus-specific CD8 + T cells favors terminal-effector differentiation in vivo. Immunity 32 (2010), 91–103.
136. Kaplan, M.H., Schindler, U., Smiley, S.T., Grusby, M.J., Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 4 (1996), 313–319.
137. Kaplan, M.H., Sun, Y.L., Hoey, T., Grusby, M.J., Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature 382 (1996), 174–177.
138. Kaplan, M.H., Wurster, A.L., Smiley, S.T., Grusby, M.J., Stat6-dependent and -independent pathways for IL-4 production. J. Immunol. 163 (1999), 6536–6540.
139. Karp, C.L., Biron, C.A., Irani, D.N., Interferon beta in multiple sclerosis: is IL-12 suppression the key?. Immunol. Today 21 (2000), 24–28.
140. Kasperkovitz, P.V., Verbeet, N.L., Smeets, T.J., Van Rietschoten, J.G., Kraan, M.C., van der Pouw Kraan, T.C., Tak, P.P., Verweij, C.L., Activation of the STAT1 pathway in rheumatoid arthritis. Ann. Rheum. Dis. 63 (2004), 233–239.
141. Kastirr, I., Maglie, S., Paroni, M., Alfen, J.S., Nizzoli, G., Sugliano, E., Crosti, M.C., Moro, M., Steckel, B., Steinfelder, S., Stolzel, K., Romagnani, C., Botti, F., Caprioli, F., Pagani, M., Abrignani, S., Geginat, J., IL-21 is a central memory T cell-associated cytokine that inhibits the generation of pathogenic Th1/17 effector cells. J. Immunol. 193 (2014), 3322–3331.
142. Keystone, E.C., Taylor, P.C., Drescher, E., Schlichting, D.E., Beattie, S.D., Berclaz, P.Y., Lee, C.H., Fidelus-Gort, R.K., Luchi, M.E., Rooney, T.P., Macias, W.L., Genovese, M.C., Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Ann. Rheum. Dis. 74 (2015), 333–340.
143. Khor, B., Gardet, A., Xavier, R.J., Genetics and pathogenesis of inflammatory bowel disease. Nature 474 (2011), 307–317.
144. Kilic, S.S., Hacimustafaoglu, M., Boisson-Dupuis, S., Kreins, A.Y., Grant, A.V., Abel, L., Casanova, J.L., A patient with tyrosine kinase 2 deficiency without hyper-IgE syndrome. J. Pediatr. 160 (2012), 1055–1057.
145. Kim, C.H., Rott, L.S., Clark-Lewis, I., Campbell, D.J., Wu, L., Butcher, E.C., Subspecialization of CXCR5 + T cells: B helper activity is focused in a germinal center-localized subset of CXCR5 + T cells. J. Exp. Med. 193 (2001), 1373–1381.
146. Kim, Y.S., Choi, S.J., Choi, J.P., Jeon, S.G., Oh, S., Lee, B.J., Gho, Y.S., Lee, C.G., Zhu, Z., Elias, J.A., Kim, Y.K., IL-12-STAT4-IFN-gamma axis is a key downstream pathway in the development of IL-13-mediated asthma phenotypes in a Th2 type asthma model. Exp. Mol. Med. 42 (2010), 533–546.
147. Klein, W., Tromm, A., Folwaczny, C., Hagedorn, M., Duerig, N., Epplen, J., Schmiegel, W., Griga, T., The G2964A polymorphism of the STAT6 gene in inflammatory bowel disease. Dig. Liver Dis. 37 (2005), 159–161.
148. Kobayashi, S., Ikari, K., Kaneko, H., Kochi, Y., Yamamoto, K., Shimane, K., Nakamura, Y., Toyama, Y., Mochizuki, T., Tsukahara, S., Kawaguchi, Y., Terai, C., Hara, M., Tomatsu, T., Yamanaka, H., Horiuchi, T., Tao, K., Yasutomo, K., Hamada, D., Yasui, N., Inoue, H., Itakura, M., Okamoto, H., Kamatani, N., Momohara, S., Association of STAT4 with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in the Japanese population. Arthritis Rheum. 58 (2008), 1940–1946.
149. Kobayashi, S., Watanabe, T., Suzuki, R., Furu, M., Ito, H., Ito, J., Matsuda, S., Yoshitomi, H., TGF-beta induces the differentiation of human CXCL13-producing CD4(+) T cells. Eur. J. Immunol. 46 (2016), 360–371.
150. Kofoed, E.M., Hwa, V., Little, B., Woods, K.A., Buckway, C.K., Tsubaki, J., Pratt, K.L., Bezrodnik, L., Jasper, H., Tepper, A., Heinrich, J.J., Rosenfeld, R.G., Growth hormone insensitivity associated with a STAT5b mutation. N. Engl. J. Med. 349 (2003), 1139–1147.
151. Kopf, M., Le Gros, G., Bachmann, M., Lamers, M.C., Bluethmann, H., Kohler, G., Disruption of the murine IL-4 gene blocks Th2 cytokine responses. Nature 362 (1993), 245–248.
152. Korman, B.D., Kastner, D.L., Gregersen, P.K., Remmers, E.F., STAT4: genetics, mechanisms, and implications for autoimmunity. Curr. Allergy Asthma Rep. 8 (2008), 398–403.
153. Korn, T., Bettelli, E., Gao, W., Awasthi, A., Jager, A., Strom, T.B., Oukka, M., Kuchroo, V.K., IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448 (2007), 484–487.
154. Kremer, J., Li, Z.G., Hall, S., Fleischmann, R., Genovese, M., Martin-Mola, E., Isaacs, J.D., Gruben, D., Wallenstein, G., Krishnaswami, S., Zwillich, S.H., Koncz, T., Riese, R., Bradley, J., Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann. Intern. Med. 159 (2013), 253–261.
155. Kudlacz, E., Conklyn, M., Andresen, C., Whitney-Pickett, C., Changelian, P., The JAK-3 inhibitor CP-690550 is a potent anti-inflammatory agent in a murine model of pulmonary eosinophilia. Eur. J. Pharmacol. 582 (2008), 154–161.
156. Kuhbacher, T., Gionchetti, P., Hampe, J., Helwig, U., Rosenstiel, P., Campieri, M., Buhr, H.J., Schreiber, S., Activation of signal-transducer and activator of transcription 1 (STAT1) in pouchitis. Clin. Exp. Immunol. 123 (2001), 395–401.
157. Kumar, N., Hanks, M.E., Chandrasekaran, P., Davis, B.C., Hsu, A.P., Van Wagoner, N.J., Merlin, J.S., Spalding, C., La Hoz, R.M., Holland, S.M., Zerbe, C.S., Sampaio, E.P., Gain-of-function signal transducer and activator of transcription 1 (STAT1) mutation-related primary immunodeficiency is associated with disseminated mucormycosis. J. Allergy Clin. Immunol. 134 (2014), 236–239.
158. Kuperman, D., Schofield, B., Wills-Karp, M., Grusby, M.J., Signal transducer and activator of transcription factor 6 (Stat6)-deficient mice are protected from antigen-induced airway hyperresponsiveness and mucus production. J. Exp. Med. 187 (1998), 939–948.
159. Kweon, M.N., Yamamoto, M., Kajiki, M., Takahashi, I., Kiyono, H., Systemically derived large intestinal CD4(+) Th2 cells play a central role in STAT6-mediated allergic diarrhea. J. Clin. Invest. 106 (2000), 199–206.
160. Laurence, A., Tato, C.M., Davidson, T.S., Kanno, Y., Chen, Z., Yao, Z., Blank, R.B., Meylan, F., Siegel, R., Hennighausen, L., Shevach, E.M., O'Shea, J.J., Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26 (2007), 371–381.
161. Le Gros, G., Ben-Sasson, S.Z., Seder, R., Finkelman, F.D., Paul, W.E., Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. J. Exp. Med. 172 (1990), 921–929.
162. Leal, R.F., Ayrizono, M.L., Milanski, M., Coope, A., Fagundes, J.J., Velloso, L.A., Coy, C.S., Activation of signal transducer and activator of transcription-1 (STAT-1) and differential expression of interferon-gamma and anti-inflammatory proteins in pelvic ileal pouches for ulcerative colitis and familial adenomatous polyposis. Clin. Exp. Immunol. 160 (2010), 380–385.
163. Lee, D.U., Rao, A., Molecular analysis of a locus control region in the T helper 2 cytokine gene cluster: a target for STAT6 but not GATA3. Proc. Natl. Acad. Sci. U.S.A. 101 (2004), 16010–16015.
164. Lee, H.S., Park, H., Yang, S., Kim, D., Park, Y., STAT4 polymorphism is associated with early-onset type 1 diabetes, but not with late-onset type 1 diabetes. Ann. N. Y. Acad. Sci. 1150 (2008), 93–98.
165. Lee, Y.K., Turner, H., Maynard, C.L., Oliver, J.R., Chen, D., Elson, C.O., Weaver, C.T., Late developmental plasticity in the T helper 17 lineage. Immunity 30 (2009), 92–107.
166. Lee, B.J., Kim, Y.J., Cho, D.H., Sohn, N.W., Kang, H., Immunomodulatory effect of water extract of cinnamon on anti-CD3-induced cytokine responses and p38, JNK, ERK1/2, and STAT4 activation. Immunopharmacol. Immunotoxicol. 33 (2011), 714–722.
167. Lee, E.B., Fleischmann, R., Hall, S., Wilkinson, B., Bradley, J.D., Gruben, D., Koncz, T., Krishnaswami, S., Wallenstein, G.V., Zang, C., Zwillich, S.H., Van Vollenhoven, R.F., ORAL Start Investigators, Tofacitinib versus methotrexate in rheumatoid arthritis. N. Engl. J. Med. 370 (2014), 2377–2386.
168. Lee, S.Y., Lee, S.H., Yang, E.J., Kim, E.K., Kim, J.K., Shin, D.Y., Cho, M.L., Metformin ameliorates inflammatory bowel disease by suppression of the STAT3 signaling pathway and regulation of the between Th17/Treg balance. PLoS One, 10, 2015, e0135858.
169. Lee, S.Y., Min, H.K., Lee, S.H., Shin, H.J., Lee, W.Y., Cho, Y.G., Kwok, S.K., Ju, J.H., Cho, M.L., Park, S.H., IL-1 receptor antagonist (IL-1Ra)-Fc ameliorate autoimmune arthritis by regulation of the Th17 cells/Treg balance and arthrogenic cytokine activation. Immunol. Lett. 172 (2016), 56–66.
170. Levy, D.E., Darnell, J.E. Jr., Stats: transcriptional control and biological impact. Nat. Rev. Mol. Cell Biol. 3 (2002), 651–662.
171. Li, L., Sad, S., Kagi, D., Mosmann, T.R., CD8Tc1 and Tc2 cells secrete distinct cytokine patterns in vitro and in vivo but induce similar inflammatory reactions. J. Immunol. 158 (1997), 4152–4161.
172. Li, M.O., Wan, Y.Y., Sanjabi, S., Robertson, A.K., Flavell, R.A., Transforming growth factor-beta regulation of immune responses. Annu. Rev. Immunol. 24 (2006), 99–146.
173. Li, J., Jie, H.B., Lei, Y., Gildener-Leapman, N., Trivedi, S., Green, T., Kane, L.P., Ferris, R.L., PD-1/SHP-2 inhibits Tc1/Th1 phenotypic responses and the activation of T cells in the tumor microenvironment. Cancer Res. 75 (2015), 508–518.
174. Liao, W., Schones, D.E., Oh, J., Cui, Y., Cui, K., Roh, T.Y., Zhao, K., Leonard, W.J., Priming for T helper type 2 differentiation by interleukin 2-mediated induction of interleukin 4 receptor alpha-chain expression. Nat. Immunol. 9 (2008), 1288–1296.
175. Liao, W., Spolski, R., Li, P., Du, N., West, E.E., Ren, M., Mitra, S., Leonard, W.J., Opposing actions of IL-2 and IL-21 on Th9 differentiation correlate with their differential regulation of BCL6 expression. Proc. Natl. Acad. Sci. U.S.A. 111 (2014), 3508–3513.
176. Lim, C.P., Cao, X., Structure, function, and regulation of STAT proteins. Mol. Biosyst. 2 (2006), 536–550.
177. Lim, H., Cho, M., Choi, G., Na, H., Chung, Y., Dynamic control of Th2 cell responses by STAT3 during allergic lung inflammation in mice. Int. Immunopharmacol. 28 (2015), 846–853.
178. Litonjua, A.A., Tantisira, K.G., Lake, S., Lazarus, R., Richter, B.G., Gabriel, S., Silverman, E.S., Weiss, S.T., Polymorphisms in signal transducer and activator of transcription 3 and lung function in asthma. Respir. Res., 6, 2005, 52.
179. Liu, Z., Geboes, K., Colpaert, S., D'Haens, G.R., Rutgeerts, P., Ceuppens, J.L., IL-15 is highly expressed in inflammatory bowel disease and regulates local T cell-dependent cytokine production. J. Immunol. 164 (2000), 3608–3615.
180. Liu, K., Liang, C., Liang, Z., Tus, K., Wakeland, E.K., Sle1ab mediates the aberrant activation of STAT3 and Ras-ERK signaling pathways in B lymphocytes. J. Immunol. 174 (2005), 1630–1637.
181. Liu, W., Putnam, A.L., Xu-Yu, Z., Szot, G.L., Lee, M.R., Zhu, S., Gottlieb, P.A., Kapranov, P., Gingeras, T.R., Fazekas de St Groth, B., Clayberger, C., Soper, D.M., Ziegler, S.F., Bluestone, J.A., CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4 + T reg cells. J. Exp. Med. 203 (2006), 1701–1711.
182. Liu, X., Lee, Y.S., Yu, C.R., Egwuagu, C.E., Loss of STAT3 in CD4 + T cells prevents development of experimental autoimmune diseases. J. Immunol. 180 (2008), 6070–6076.
183. Liu, L., Okada, S., Kong, X.F., Kreins, A.Y., Cypowyj, S., Abhyankar, A., Toubiana, J., Itan, Y., Audry, M., Nitschke, P., Masson, C., Toth, B., Flatot, J., Migaud, M., Chrabieh, M., Kochetkov, T., Bolze, A., Borghesi, A., Toulon, A., Hiller, J., Eyerich, S., Eyerich, K., Gulacsy, V., Chernyshova, L., Chernyshov, V., Bondarenko, A., Grimaldo, R.M., Blancas-Galicia, L., Beas, I.M., Roesler, J., Magdorf, K., Engelhard, D., Thumerelle, C., Burgel, P.R., Hoernes, M., Drexel, B., Seger, R., Kusuma, T., Jansson, A.F., Sawalle-Belohradsky, J., Belohradsky, B., Jouanguy, E., Bustamante, J., Bue, M., Karin, N., Wildbaum, G., Bodemer, C., Lortholary, O., Fischer, A., Blanche, S., Al-Muhsen, S., Reichenbach, J., Kobayashi, M., Rosales, F.E., Lozano, C.T., Kilic, S.S., Oleastro, M., Etzioni, A., Traidl-Hoffmann, C., Renner, E.D., Abel, L., Picard, C., Marodi, L., Boisson-Dupuis, S., Puel, A., Casanova, J.L., Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J. Exp. Med. 208 (2011), 1635–1648.
184. Liu, Q.F., Li, Y., Zhao, Q.H., Wang, Z.Y., Hu, S., Yang, C.Q., Ye, K., Li, L., Association of STAT4 rs7574865 polymorphism with susceptibility to inflammatory bowel disease: a systematic review and meta-analysis. Clin. Res. Hepatol. Gastroenterol. 39 (2015), 627–636.
185. Lu, L.F., Boldin, M.P., Chaudhry, A., Lin, L.L., Taganov, K.D., Hanada, T., Yoshimura, A., Baltimore, D., Rudensky, A.Y., Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 142 (2010), 914–929.
186. Lu, X., Du, J., Liang, J., Zhu, X., Yang, Y., Xu, J., Transcriptional regulatory network for psoriasis. J. Dermatol. 40 (2013), 48–53.
187. Lu, Y., Hong, B., Li, H., Zheng, Y., Zhang, M., Wang, S., Qian, J., Yi, Q., Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers. Proc. Natl. Acad. Sci. U.S.A. 111 (2014), 2265–2270.
188. Luhrmann, A., Tschernig, T., Von Der Leyen, H., Hecker, M., Pabst, R., Wagner, A.H., Decoy oligodeoxynucleotide against STAT transcription factors decreases allergic inflammation in a rat asthma model. Exp. Lung Res. 36 (2010), 85–93.
189. Lupardus, P.J., Skiniotis, G., Rice, A.J., Thomas, C., Fischer, S., Walz, T., Garcia, K.C., Structural snapshots of full-length Jak1, a transmembrane gp130/IL-6/IL-6Ralpha cytokine receptor complex, and the receptor-Jak1 holocomplex. Structure 19 (2011), 45–55.
190. Ma, J., Cao, X., Regulation of Stat3 nuclear import by importin alpha5 and importin alpha7 via two different functional sequence elements. Cell. Signal. 18 (2006), 1117–1126.
191. Ma, C.S., Chew, G.Y., Simpson, N., Priyadarshi, A., Wong, M., Grimbacher, B., Fulcher, D.A., Tangye, S.G., Cook, M.C., Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J. Exp. Med. 205 (2008), 1551–1557.
192. Macchi, P., Villa, A., Giliani, S., Sacco, M.G., Frattini, A., Porta, F., Ugazio, A.G., Johnston, J.A., Candotti, F., O'Shea, J.J., et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 377 (1995), 65–68.
193. Malek, T.R., Bayer, A.L., Tolerance, not immunity, crucially depends on IL-2. Nat. Rev. Immunol. 4 (2004), 665–674.
194. Malek, T.R., Yu, A., Vincek, V., Scibelli, P., Kong, L., CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17 (2002), 167–178.
195. Mangan, P.R., Harrington, L.E., O'Quinn, D.B., Helms, W.S., Bullard, D.C., Elson, C.O., Hatton, R.D., Wahl, S.M., Schoeb, T.R., Weaver, C.T., Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441 (2006), 231–234.
196. Mari, N., Hercor, M., Denanglaire, S., Leo, O., Andris, F., The capacity of Th2 lymphocytes to deliver B-cell help requires expression of the transcription factor STAT3. Eur. J. Immunol. 43 (2013), 1489–1498.
197. Mathew, A., Maclean, J.A., Dehaan, E., Tager, A.M., Green, F.H., Luster, A.D., Signal transducer and activator of transcription 6 controls chemokine production and T helper cell type 2 cell trafficking in allergic pulmonary inflammation. J. Exp. Med. 193 (2001), 1087–1096.
198. Mathur, A.N., Chang, H.C., Zisoulis, D.G., Stritesky, G.L., Yu, Q., O'Malley, J.T., Kapur, R., Levy, D.E., Kansas, G.S., Kaplan, M.H., Stat3 and Stat4 direct development of IL-17-secreting Th cells. J. Immunol. 178 (2007), 4901–4907.
199. Matsubara, S., Takeda, K., Kodama, T., Joetham, A., Miyahara, N., Koya, T., Swasey, C.H., Okamoto, M., Dakhama, A., Gelfand, E.W., IL-2 and IL-18 attenuation of airway hyperresponsiveness requires STAT4, IFN-gamma, and natural killer cells. Am. J. Respir. Cell Mol. Biol. 36 (2007), 324–332.
200. Mazzarella, G., MacDonald, T.T., Salvati, V.M., Mulligan, P., Pasquale, L., Stefanile, R., Lionetti, P., Auricchio, S., Pallone, F., Troncone, R., Monteleone, G., Constitutive activation of the signal transducer and activator of transcription pathway in celiac disease lesions. Am. J. Pathol. 162 (2003), 1845–1855.
201. Mcgeachy, M.J., Bak-Jensen, K.S., Chen, Y., Tato, C.M., Blumenschein, W., McClanahan, T., Cua, D.J., TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat. Immunol. 8 (2007), 1390–1397.
202. Mchugh, R.S., Whitters, M.J., Piccirillo, C.A., Young, D.A., Shevach, E.M., Collins, M., Byrne, M.C., CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16 (2002), 311–323.
203. Mcneill, A., Spittle, E., Backstrom, B.T., Partial depletion of CD69low-expressing natural regulatory T cells with the anti-CD25 monoclonal antibody PC61. Scand. J. Immunol. 65 (2007), 63–69.
204. Mcwilliams, I.L., Rajbhandari, R., Nozell, S., Benveniste, E., Harrington, L.E., STAT4 controls GM-CSF production by both Th1 and Th17 cells during EAE. J. Neuroinflammation, 12, 2015, 128.
205. Medzhitov, R., Recognition of microorganisms and activation of the immune response. Nature 449 (2007), 819–826.
206. Mehta, D.S., Wurster, A.L., Grusby, M.J., Biology of IL-21 and the IL-21 receptor. Immunol. Rev. 202 (2004), 84–95.
207. Mertens, C., Darnell, J.E. Jr., SnapShot: JAK-STAT signaling. Cell, 131, 2007, 612.
208. Mesa, R.A., Ruxolitinib, a selective JAK1 and JAK2 inhibitor for the treatment of myeloproliferative neoplasms and psoriasis. IDrugs 13 (2010), 394–403.
209. Mesa, R.A., Yasothan, U., Kirkpatrick, P., Ruxolitinib. Nat. Rev. Drug Discov. 11 (2012), 103–104.
210. Meyer, T., Vinkemeier, U., Nucleocytoplasmic shuttling of STAT transcription factors. Eur. J. Biochem. 271 (2004), 4606–4612.
211. Meyer, D.M., Jesson, M.I., Li, X., Elrick, M.M., Funckes-Shippy, C.L., Warner, J.D., Gross, C.J., Dowty, M.E., Ramaiah, S.K., Hirsch, J.L., Saabye, M.J., Barks, J.L., Kishore, N., Morris, D.L., Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J. Inflamm. (Lond.), 7, 2010, 41.
212. Mikhak, Z., Fleming, C.M., Medoff, B.D., Thomas, S.Y., Tager, A.M., Campanella, G.S., Luster, A.D., STAT1 in peripheral tissue differentially regulates homing of antigen-specific Th1 and Th2 cells. J. Immunol. 176 (2006), 4959–4967.
213. Milner, J.D., Holland, S.M., The cup runneth over: lessons from the ever-expanding pool of primary immunodeficiency diseases. Nat. Rev. Immunol. 13 (2013), 635–648.
214. Milner, J.D., Brenchley, J.M., Laurence, A., Freeman, A.F., Hill, B.J., Elias, K.M., Kanno, Y., Spalding, C., Elloumi, H.Z., Paulson, M.L., Davis, J., Hsu, A., Asher, A.I., O'Shea, J., Holland, S.M., Paul, W.E., Douek, D.C., Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452 (2008), 773–776.
215. Milner, J.D., Vogel, T.P., Forbes, L., Ma, C.A., Stray-Pedersen, A., Niemela, J.E., Lyons, J.J., Engelhardt, K.R., Zhang, Y., Topcagic, N., Roberson, E.D., Matthews, H., Verbsky, J.W., Dasu, T., Vargas-Hernandez, A., Varghese, N., Mcclain, K.L., Karam, L.B., Nahmod, K., Makedonas, G., Mace, E.M., Sorte, H.S., Perminow, G., Rao, V.K., O'Connell, M.P., Price, S., Su, H.C., Butrick, M., Mcelwee, J., Hughes, J.D., Willet, J., Swan, D., Xu, Y., Santibanez-Koref, M., Slowik, V., Dinwiddie, D.L., Ciaccio, C.E., Saunders, C.J., Septer, S., Kingsmore, S.F., White, A.J., Cant, A.J., Hambleton, S., Cooper, M.A., Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood 125 (2015), 591–599.
216. Minegishi, Y., Saito, M., Morio, T., Watanabe, K., Agematsu, K., Tsuchiya, S., Takada, H., Hara, T., Kawamura, N., Ariga, T., Kaneko, H., Kondo, N., Tsuge, I., Yachie, A., Sakiyama, Y., Iwata, T., Bessho, F., Ohishi, T., Joh, K., Imai, K., Kogawa, K., Shinohara, M., Fujieda, M., Wakiguchi, H., Pasic, S., Abinun, M., Ochs, H.D., Renner, E.D., Jansson, A., Belohradsky, B.H., Metin, A., Shimizu, N., Mizutani, S., Miyawaki, T., Nonoyama, S., Karasuyama, H., Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 25 (2006), 745–755.
217. Mishra, A., Rothenberg, M.E., Intratracheal IL-13 induces eosinophilic esophagitis by an IL-5, eotaxin-1, and STAT6-dependent mechanism. Gastroenterology 125 (2003), 1419–1427.
218. Mitchell, E., Jones, G., Subcutaneous tocilizumab for the treatment of rheumatoid arthritis. Expert Rev. Clin. Immunol. 12 (2016), 103–114.
219. Miyata, S., Matsuyama, T., Kodama, T., Nishioka, Y., Kuribayashi, K., Takeda, K., Akira, S., Sugita, M., STAT6 deficiency in a mouse model of allergen-induced airways inflammation abolishes eosinophilia but induces infiltration of CD8 + T cells. Clin. Exp. Allergy 29 (1999), 114–123.
220. Mogensen, T.H., STAT3 and the Hyper-IgE syndrome: clinical presentation, genetic origin, pathogenesis, novel findings and remaining uncertainties. JAKSTAT, 2, 2013, e23435.
221. Moore, K.W., de Waal Malefyt, R., Coffman, R.L., O'Garra, A., Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19 (2001), 683–765.
222. Mori, T., Miyamoto, T., Yoshida, H., Asakawa, M., Kawasumi, M., Kobayashi, T., Morioka, H., Chiba, K., Toyama, Y., Yoshimura, A., IL-1beta and TNFalpha-initiated IL-6-STAT3 pathway is critical in mediating inflammatory cytokines and RANKL expression in inflammatory arthritis. Int. Immunol. 23 (2011), 701–712.
223. Mosmann, T.R., Li, L., Sad, S., Functions of CD8 T-cell subsets secreting different cytokine patterns. Semin. Immunol. 9 (1997), 87–92.
224. Mudter, J., Weigmann, B., Bartsch, B., Kiesslich, R., Strand, D., Galle, P.R., Lehr, H.A., Schmidt, J., Neurath, M.F., Activation pattern of signal transducers and activators of transcription (STAT) factors in inflammatory bowel diseases. Am. J. Gastroenterol. 100 (2005), 64–72.
225. Muller, J., Sperl, B., Reindl, W., Kiessling, A., Berg, T., Discovery of chromone-based inhibitors of the transcription factor STAT5. Chembiochem 9 (2008), 723–727.
226. Musso, T., Johnston, J.A., Linnekin, D., Varesio, L., Rowe, T.K., O'Shea, J.J., Mcvicar, D.W., Regulation of JAK3 expression in human monocytes: phosphorylation in response to interleukins 2, 4, and 7. J. Exp. Med. 181 (1995), 1425–1431.
227. Musso, A., Dentelli, P., Carlino, A., Chiusa, L., Repici, A., Sturm, A., Fiocchi, C., Rizzetto, M., Pegoraro, L., Sategna-Guidetti, C., Brizzi, M.F., Signal transducers and activators of transcription 3 signaling pathway: an essential mediator of inflammatory bowel disease and other forms of intestinal inflammation. Inflamm. Bowel Dis. 11 (2005), 91–98.
228. Nagashima, S., Nagata, H., Iwata, M., Yokota, M., Moritomo, H., Orita, M., Kuromitsu, S., Koakutsu, A., Ohga, K., Takeuchi, M., Ohta, M., Tsukamoto, S., Identification of 4-benzylamino-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide derivatives as potent and orally bioavailable STAT6 inhibitors. Bioorg. Med. Chem. 16 (2008), 6509–6521.
229. Nagashima, S., Hondo, T., Nagata, H., Ogiyama, T., Maeda, J., Hoshii, H., Kontani, T., Kuromitsu, S., Ohga, K., Orita, M., Ohno, K., Moritomo, A., Shiozuka, K., Furutani, M., Takeuchi, M., Ohta, M., Tsukamoto, S., Novel 7H-pyrrolo[2,3-d]pyrimidine derivatives as potent and orally active STAT6 inhibitors. Bioorg. Med. Chem. 17 (2009), 6926–6936.
230. Nakayamada, S., Kanno, Y., Takahashi, H., Jankovic, D., Lu, K.T., Johnson, T.A., Sun, H.W., Vahedi, G., Hakim, O., Handon, R., Schwartzberg, P.L., Hager, G.L., O'Shea, J.J., Early Th1 cell differentiation is marked by a Tfh cell-like transition. Immunity 35 (2011), 919–931.
231. Nakayamada, S., Poholek, A.C., Lu, K.T., Takahashi, H., Kato, M., Iwata, S., Hirahara, K., Cannons, J.L., Schwartzberg, P.L., Vahedi, G., Sun, H.W., Kanno, Y., O'Shea, J.J., Type I IFN induces binding of STAT1 to Bcl6: divergent roles of STAT family transcription factors in the T follicular helper cell genetic program. J. Immunol. 192 (2014), 2156–2166.
232. Nam, S., Scuto, A., Yang, F., Chen, W., Park, S., Yoo, H.S., Konig, H., Bhatia, R., Cheng, X., Merz, K.H., Eisenbrand, G., Jove, R., Indirubin derivatives induce apoptosis of chronic myelogenous leukemia cells involving inhibition of Stat5 signaling. Mol. Oncol. 6 (2012), 276–283.
233. Nelson, E.A., Walker, S.R., Weisberg, E., Bar-Natan, M., Barrett, R., Gashin, L.B., Terrell, S., Klitgaard, J.L., Santo, L., Addorio, M.R., Ebert, B.L., Griffin, J.D., Frank, D.A., The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors. Blood 117 (2011), 3421–3429.
234. Neurath, M.F., Cytokines in inflammatory bowel disease. Nat. Rev. Immunol. 14 (2014), 329–342.
235. Nguyen, P.M., Putoczki, T.L., Ernst, M., STAT3-activating cytokines: a therapeutic opportunity for inflammatory bowel disease?. J. Interferon Cytokine Res. 35 (2015), 340–350.
236. Niedbala, W., Besnard, A.G., Nascimento, D.C., Donate, P.B., Sonego, F., Yip, E., Guabiraba, R., Chang, H.D., Fukada, S.Y., Salmond, R.J., Schmitt, E., Bopp, T., Ryffel, B., Liew, F.Y., Nitric oxide enhances Th9 cell differentiation and airway inflammation. Nat. Commun., 5, 2014, 4575.
237. Nishibori, T., Tanabe, Y., Su, L., David, M., Impaired development of CD4 + CD25 + regulatory T cells in the absence of STAT1: increased susceptibility to autoimmune disease. J. Exp. Med. 199 (2004), 25–34.
238. Nishikomori, R., Usui, T., Wu, C.Y., Morinobu, A., O'Shea, J.J., Strober, W., Activated STAT4 has an essential role in Th1 differentiation and proliferation that is independent of its role in the maintenance of IL-12R beta 2 chain expression and signaling. J. Immunol. 169 (2002), 4388–4398.
239. Noguchi, M., Yi, H., Rosenblatt, H.M., Filipovich, A.H., Adelstein, S., Modi, W.S., Mcbride, O.W., Leonard, W.J., Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 73 (1993), 147–157.
240. Nurieva, R., Yang, X.O., Martinez, G., Zhang, Y., Panopoulos, A.D., Ma, L., Schluns, K., Tian, Q., Watowich, S.S., Jetten, A.M., Dong, C., Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448 (2007), 480–483.
241. Nurieva, R.I., Chung, Y., Hwang, D., Yang, X.O., Kang, H.S., Ma, L., Wang, Y.H., Watowich, S.S., Jetten, A.M., Tian, Q., Dong, C., Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29 (2008), 138–149.
242. Nurieva, R.I., Podd, A., Chen, Y., Alekseev, A.M., Yu, M., Qi, X., Huang, H., Wen, R., Wang, J., Li, H.S., Watowich, S.S., Qi, H., Dong, C., Wang, D., STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function. J. Biol. Chem. 287 (2012), 11234–11239.
243. Obermeier, F., Hausmann, M., Kellermeier, S., Kiessling, S., Strauch, U.G., Duitman, E., Bulfone-Paus, S., Herfarth, H., Bock, J., Dunger, N., Stoeck, M., Scholmerich, J., Falk, W., Rogler, G., IL-15 protects intestinal epithelial cells. Eur. J. Immunol. 36 (2006), 2691–2699.
244. Olson, M.R., Verdan, F.F., Hufford, M.M., Dent, A.L., Kaplan, M.H., STAT3 impairs STAT5 activation in the development of IL-9-secreting T cells. J. Immunol. 196 (2016), 3297–3304.
245. O'Malley, J.T., Eri, R.D., Stritesky, G.L., Mathur, A.N., Chang, H.C., Hogenesch, H., Srinivasan, M., Kaplan, M.H., STAT4 isoforms differentially regulate Th1 cytokine production and the severity of inflammatory bowel disease. J. Immunol. 181 (2008), 5062–5070.
246. O'Malley, J.T., Sehra, S., Thieu, V.T., Yu, Q., Chang, H.C., Stritesky, G.L., Nguyen, E.T., Mathur, A.N., Levy, D.E., Kaplan, M.H., Signal transducer and activator of transcription 4 limits the development of adaptive regulatory T cells. Immunology 127 (2009), 587–595.
247. Ordas, I., Eckmann, L., Talamini, M., Baumgart, D.C., Sandborn, W.J., Ulcerative colitis. Lancet 380 (2012), 1606–1619.
248. O'Reilly, S., Ciechomska, M., Fullard, N., Przyborski, S., Van Laar, J.M., IL-13 mediates collagen deposition via STAT6 and microRNA-135b: a role for epigenetics. Sci. Rep., 6, 2016, 25066.
249. Orozco, G., Alizadeh, B.Z., Delgado-Vega, A.M., Gonzalez-Gay, M.A., Balsa, A., Pascual-Salcedo, D., Fernandez-Gutierrez, B., Gonzalez-Escribano, M.F., Petersson, I.F., Van Riel, P.L., Barrera, P., Coenen, M.J., Radstake, T.R., Van Leeuwen, M.A., Wijmenga, C., Koeleman, B.P., Alarcon-Riquelme, M., Martin, J., Association of STAT4 with rheumatoid arthritis: a replication study in three European populations. Arthritis Rheum. 58 (2008), 1974–1980.
250. O'Shea, J.J., Paul, W.E., Mechanisms underlying lineage commitment and plasticity of helper CD4 + T cells. Science 327 (2010), 1098–1102.
251. O'Shea, J.J., Holland, S.M., Staudt, L.M., JAKs and STATs in immunity, immunodeficiency, and cancer. N. Engl. J. Med. 368 (2013), 161–170.
252. O'Shea, J.J., Kontzias, A., Yamaoka, K., Tanaka, Y., Laurence, A., Janus kinase inhibitors in autoimmune diseases. Ann. Rheum. Dis. 72:Suppl. 2 (2013), ii111–ii115.
253. Ouyang, W., Jacobson, N.G., Bhattacharya, D., Gorham, J.D., Fenoglio, D., Sha, W.C., Murphy, T.L., Murphy, K.M., The Ets transcription factor ERM is Th1-specific and induced by IL-12 through a Stat4-dependent pathway. Proc. Natl. Acad. Sci. U.S.A. 96 (1999), 3888–3893.
254. Pallandre, J.R., Brillard, E., Crehange, G., Radlovic, A., Remy-Martin, J.P., Saas, P., Rohrlich, P.S., Pivot, X., Ling, X., Tiberghien, P., Borg, C., Role of STAT3 in CD4 + CD25 + FOXP3 + regulatory lymphocyte generation: implications in graft-versus-host disease and antitumor immunity. J. Immunol. 179 (2007), 7593–7604.
255. Pandiyan, P., Yang, X.P., Saravanamuthu, S.S., Zheng, L., Ishihara, S., O'Shea, J.J., Lenardo, M.J., The role of IL-15 in activating STAT5 and fine-tuning IL-17A production in CD4 T lymphocytes. J. Immunol. 189 (2012), 4237–4246.
256. Panes, J., Su, C., Bushmakin, A.G., Cappelleri, J.C., Mamolo, C., Healey, P., Randomized trial of tofacitinib in active ulcerative colitis: analysis of efficacy based on patient-reported outcomes. BMC Gastroenterol., 15, 2015, 14.
257. Pang, Y.H., Zheng, C.Q., Yang, X.Z., Zhang, W.J., Increased expression and activation of IL-12-induced Stat4 signaling in the mucosa of ulcerative colitis patients. Cell. Immunol. 248 (2007), 115–120.
258. Papp, K.A., Menter, A., Strober, B., Langley, R.G., Buonanno, M., Wolk, R., Gupta, P., Krishnaswami, S., Tan, H., Harness, J.A., Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a phase 2b randomized placebo-controlled dose-ranging study. Br. J. Dermatol. 167 (2012), 668–677.
259. Papp, K.A., Menter, M.A., Abe, M., Elewski, B., Feldman, S.R., Gottlieb, A.B., Langley, R., Luger, T., Thaci, D., Buonanno, M., Gupta, P., Proulx, J., Lan, S., Wolk, R., Pivotal, O.P.T., Investigators, O.P.T.P., Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two randomized, placebo-controlled, phase III trials. Br. J. Dermatol. 173 (2015), 949–961.
260. Papp, K., Menter, M.A., Raman, M., Disch, D., Schlichting, D.E., Gaich, C., Macias, W., Zhang, X., Janes, J.M., A randomized phase 2b trial of baricitinib, an oral JAK1/JAK2 inhibitor, in patients with moderate-to-severe psoriasis. Br. J. Dermatol. 174 (2016), 1266–1276.
261. Paris, D., Beaulieu-Abdelahad, D., Abdullah, L., Bachmeier, C., Ait-Ghezala, G., Reed, J., Verma, M., Crawford, F., Mullan, M., Anti-inflammatory activity of anatabine via inhibition of STAT3 phosphorylation. Eur. J. Pharmacol. 698 (2013), 145–153.
262. Park, B.L., Cheong, H.S., Kim, L.H., Choi, Y.H., Namgoong, S., Park, H.S., Hong, S.J., Choi, B.W., Lee, J.H., Park, C.S., Shin, H.D., Association analysis of signal transducer and activator of transcription 4 (STAT4) polymorphisms with asthma. J. Hum. Genet. 50 (2005), 133–138.
263. Park, Y., Lee, H.S., Park, Y., Min, D., Yang, S., Kim, D., Cho, B., Evidence for the role of STAT4 as a general autoimmunity locus in the Korean population. Diabetes Metab. Res. Rev. 27 (2011), 867–871.
264. Park, J.S., Lim, M.A., Cho, M.L., Ryu, J.G., Moon, Y.M., Jhun, J.Y., Byun, J.K., Kim, E.K., Hwang, S.Y., Ju, J.H., Kwok, S.K., Kim, H.Y., p53 controls autoimmune arthritis via STAT-mediated regulation of the Th17 cell/Treg cell balance in mice. Arthritis Rheum. 65 (2013), 949–959.
265. Park, J.S., Kwok, S.K., Lim, M.A., Kim, E.K., Ryu, J.G., Kim, S.M., Oh, H.J., Ju, J.H., Park, S.H., Kim, H.Y., Cho, M.L., STA-21, a promising STAT-3 inhibitor that reciprocally regulates Th17 and Treg cells, inhibits osteoclastogenesis in mice and humans and alleviates autoimmune inflammation in an experimental model of rheumatoid arthritis. Arthritis Rheumatol. 66 (2014), 918–929.
266. Park, J.S., Lee, J., Lim, M.A., Kim, E.K., Kim, S.M., Ryu, J.G., Lee, J.H., Kwok, S.K., Park, K.S., Kim, H.Y., Park, S.H., Cho, M.L., JAK2-STAT3 blockade by AG490 suppresses autoimmune arthritis in mice via reciprocal regulation of regulatory T Cells and Th17 cells. J. Immunol. 192 (2014), 4417–4424.
267. Paul, W.E., Seder, R.A., Lymphocyte responses and cytokines. Cell 76 (1994), 241–251.
268. Paul, W.E., Zhu, J., How are T(H)2-type immune responses initiated and amplified?. Nat. Rev. Immunol. 10 (2010), 225–235.
269. Paulson, M., Pisharody, S., Pan, L., Guadagno, S., Mui, A.L., Levy, D.E., Stat protein transactivation domains recruit p300/CBP through widely divergent sequences. J. Biol. Chem. 274 (1999), 25343–25349.
270. Pesce, J., Kaviratne, M., Ramalingam, T.R., Thompson, R.W., Urban, J.F. Jr., Cheever, A.W., Young, D.A., Collins, M., Grusby, M.J., Wynn, T.A., The IL-21 receptor augments Th2 effector function and alternative macrophage activation. J. Clin. Invest. 116 (2006), 2044–2055.
271. Peters, A., Fowler, K.D., Chalmin, F., Merkler, D., Kuchroo, V.K., Pot, C., IL-27 induces Th17 differentiation in the absence of STAT1 signaling. J. Immunol. 195 (2015), 4144–4153.
272. Pham, D., Yu, Q., Walline, C.C., Muthukrishnan, R., Blum, J.S., Kaplan, M.H., Opposing roles of STAT4 and Dnmt3a in Th1 gene regulation. J. Immunol. 191 (2013), 902–911.
273. Pinto, L.A., Steudemann, L., Depner, M., Klopp, N., Illig, T., Weiland, S.K., Von Mutius, E., Kabesch, M., STAT1 gene variations, IgE regulation and atopy. Allergy 62 (2007), 1456–1461.
274. Pipkin, M.E., Sacks, J.A., Cruz-Guilloty, F., Lichtenheld, M.G., Bevan, M.J., Rao, A., Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity 32 (2010), 79–90.
275. Punwani, N., Scherle, P., Flores, R., Shi, J., Liang, J., Yeleswaram, S., Levy, R., Williams, W., Gottlieb, A., Preliminary clinical activity of a topical JAK1/2 inhibitor in the treatment of psoriasis. J. Am. Acad. Dermatol. 67 (2012), 658–664.
276. Qin, H., Yeh, W.I., De Sarno, P., Holdbrooks, A.T., Liu, Y., Muldowney, M.T., Reynolds, S.L., Yanagisawa, L.L., Fox, T.H. 3rd., Park, K., Harrington, L.E., Raman, C., Benveniste, E.N., Signal transducer and activator of transcription-3/suppressor of cytokine signaling-3 (STAT3/SOCS3) axis in myeloid cells regulates neuroinflammation. Proc. Natl. Acad. Sci. U.S.A. 109 (2012), 5004–5009.
277. Quigley, M., Huang, X., Yang, Y., STAT1 signaling in CD8 T cells is required for their clonal expansion and memory formation following viral infection in vivo. J. Immunol. 180 (2008), 2158–2164.
278. Raman, K., Kaplan, M.H., Hogaboam, C.M., Berlin, A., Lukacs, N.W., STAT4 signal pathways regulate inflammation and airway physiology changes in allergic airway inflammation locally via alteration of chemokines. J. Immunol. 170 (2003), 3859–3865.
279. Ray, J.P., Marshall, H.D., Laidlaw, B.J., Staron, M.M., Kaech, S.M., Craft, J., Transcription factor STAT3 and type I interferons are corepressive insulators for differentiation of follicular helper and T helper 1 cells. Immunity 40 (2014), 367–377.
280. Read, S., Malmstrom, V., Powrie, F., Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J. Exp. Med. 192 (2000), 295–302.
281. Remmers, E.F., Plenge, R.M., Lee, A.T., Graham, R.R., Hom, G., Behrens, T.W., De Bakker, P.I., Le, J.M., Lee, H.S., Batliwalla, F., LI, W., Masters, S.L., Booty, M.G., Carulli, J.P., Padyukov, L., Alfredsson, L., Klareskog, L., Chen, W.V., Amos, C.I., Criswell, L.A., Seldin, M.F., Kastner, D.L., Gregersen, P.K., STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N. Engl. J. Med. 357 (2007), 977–986.
282. Ren, Y., Lu, L., Guo, T.B., Qiu, J., Yang, Y., Liu, A., Zhang, J.Z., Novel immunomodulatory properties of berbamine through selective down-regulation of STAT4 and action of IFN-gamma in experimental autoimmune encephalomyelitis. J. Immunol. 181 (2008), 1491–1498.
283. Rolf, J., Bell, S.E., Kovesdi, D., Janas, M.L., Soond, D.R., Webb, L.M., Santinelli, S., Saunders, T., Hebeis, B., Killeen, N., Okkenhaug, K., Turner, M., Phosphoinositide 3-kinase activity in T cells regulates the magnitude of the germinal center reaction. J. Immunol. 185 (2010), 4042–4052.
284. Romagnani, S., T-cell subsets (Th1 versus Th2). Ann. Allergy Asthma Immunol. 85 (2000), 9–18 quiz 18, 21.
285. Rosen, M.J., Frey, M.R., Washington, M.K., Chaturvedi, R., Kuhnhein, L.A., Matta, P., Revetta, F.L., Wilson, K.T., Polk, D.B., STAT6 activation in ulcerative colitis: a new target for prevention of IL-13-induced colon epithelial cell dysfunction. Inflamm. Bowel Dis. 17 (2011), 2224–2234.
286. Rosen, M.J., Chaturvedi, R., Washington, M.K., Kuhnhein, L.A., Moore, P.D., Coggeshall, S.S., McDonough, E.M., Weitkamp, J.H., Singh, A.B., Coburn, L.A., Williams, C.S., Yan, F., Van Kaer, L., Peebles, R.S. Jr., Wilson, K.T., STAT6 deficiency ameliorates severity of oxazolone colitis by decreasing expression of claudin-2 and Th2-inducing cytokines. J. Immunol. 190 (2013), 1849–1858.
287. Sad, S., Marcotte, R., Mosmann, T.R., Cytokine-induced differentiation of precursor mouse CD8 + T cells into cytotoxic CD8 + T cells secreting Th1 or Th2 cytokines. Immunity 2 (1995), 271–279.
288. Sahoo, A., Alekseev, A., Tanaka, K., Obertas, L., Lerman, B., Haymaker, C., Clise-Dwyer, K., Mcmurray, J.S., Nurieva, R., Batf is important for IL-4 expression in T follicular helper cells. Nat. Commun., 6, 2015, 7997.
289. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M., Toda, M., Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155 (1995), 1151–1164.
290. Sampath, D., Castro, M., Look, D.C., Holtzman, M.J., Constitutive activation of an epithelial signal transducer and activator of transcription (STAT) pathway in asthma. J. Clin. Invest. 103 (1999), 1353–1361.
291. Sandborn, W.J., Ghosh, S., Panes, J., Vranic, I., Su, C., Rousell, S., Niezychowski, W., Study, A.I., Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N. Engl. J. Med. 367 (2012), 616–624.
292. Sasaki, K., Zhao, X., Pardee, A.D., Ueda, R., Fujita, M., Sehra, S., Kaplan, M.H., Kane, L.P., Okada, H., Storkus, W.J., Stat6 signaling suppresses VLA-4 expression by CD8 + T cells and limits their ability to infiltrate tumor lesions in vivo. J. Immunol. 181 (2008), 104–108.
293. Sato, T., Saito, R., Jinushi, T., Tsuji, T., Matsuzaki, J., Koda, T., Nishimura, S., Takeshima, H., Nishimura, T., IFN-gamma-induced SOCS-1 regulates STAT6-dependent eotaxin production triggered by IL-4 and TNF-alpha. Biochem. Biophys. Res. Commun. 314 (2004), 468–475.
294. Schaerli, P., Willimann, K., Lang, A.B., Lipp, M., Loetscher, P., Moser, B., CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J. Exp. Med. 192 (2000), 1553–1562.
295. Schindler, C., Levy, D.E., Decker, T., JAK-STAT signaling: from interferons to cytokines. J. Biol. Chem. 282 (2007), 20059–20063.
296. Schmitt, N., Liu, Y., Bentebibel, S.E., Munagala, I., Bourdery, L., Venuprasad, K., Banchereau, J., Ueno, H., The cytokine TGF-beta co-opts signaling via STAT3-STAT4 to promote the differentiation of human TFH cells. Nat. Immunol. 15 (2014), 856–865.
297. Schneider, R., Yaneva, T., Beauseigle, D., El-Khoury, L., Arbour, N., IL-27 increases the proliferation and effector functions of human naive CD8 + T lymphocytes and promotes their development into Tc1 cells. Eur. J. Immunol. 41 (2011), 47–59.
298. Schreiber, S., Rosenstiel, P., Hampe, J., Nikolaus, S., Groessner, B., Schottelius, A., Kuhbacher, T., Hamling, J., Folsch, U.R., Seegert, D., Activation of signal transducer and activator of transcription (STAT) 1 in human chronic inflammatory bowel disease. Gut 51 (2002), 379–385.
299. Schumann, R.R., Kirschning, C.J., Unbehaun, A., Aberle, H.P., Knope, H.P., Lamping, N., Ulevitch, R.J., Herrmann, F., The lipopolysaccharide-binding protein is a secretory class 1 acute-phase protein whose gene is transcriptionally activated by APRF/STAT/3 and other cytokine-inducible nuclear proteins. Mol. Cell. Biol. 16 (1996), 3490–3503.
300. Schwarze, J., Hamelmann, E., Bradley, K.L., Takeda, K., Gelfand, E.W., Respiratory syncytial virus infection results in airway hyperresponsiveness and enhanced airway sensitization to allergen. J. Clin. Invest. 100 (1997), 226–233.
301. Seddiki, N., Santner-Nanan, B., Martinson, J., Zaunders, J., Sasson, S., Landay, A., Solomon, M., Selby, W., Alexander, S.I., Nanan, R., Kelleher, A., Fazekas De St Groth, B., Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J. Exp. Med. 203 (2006), 1693–1700.
302. Sehra, S., Bruns, H.A., Ahyi, A.N., Nguyen, E.T., Schmidt, N.W., Michels, E.G., Von Bulow, G.U., Kaplan, M.H., IL-4 is a critical determinant in the generation of allergic inflammation initiated by a constitutively active Stat6. J. Immunol. 180 (2008), 3551–3559.
303. Seto, Y., Nakajima, H., Suto, A., Shimoda, K., Saito, Y., Nakayama, K.I., Iwamoto, I., Enhanced Th2 cell-mediated allergic inflammation in Tyk2-deficient mice. J. Immunol. 170 (2003), 1077–1083.
304. Shale, M., Schiering, C., Powrie, F., CD4(+) T-cell subsets in intestinal inflammation. Immunol. Rev. 252 (2013), 164–182.
305. Shao, W.H., Gamero, A.M., Zhen, Y., Lobue, M.J., Priest, S.O., Albandar, H.J., Cohen, P.L., Stat1 regulates lupus-like chronic graft-versus-host disease severity via interactions with Stat3. J. Immunol. 195 (2015), 4136–4143.
306. Sheng, W., Yang, F., Zhou, Y., Yang, H., Low, P.Y., Kemeny, D.M., Tan, P., Moh, A., Kaplan, M.H., Zhang, Y., Fu, X.Y., STAT5 programs a distinct subset of GM-CSF-producing T helper cells that is essential for autoimmune neuroinflammation. Cell Res. 24 (2014), 1387–1402.
307. Shimoda, K., Van Deursen, J., Sangster, M.Y., Sarawar, S.R., Carson, R.T., Tripp, R.A., Chu, C., Quelle, F.W., Nosaka, T., Vignali, D.A., Doherty, P.C., Grosveld, G., Paul, W.E., Ihle, J.N., Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 380 (1996), 630–633.
308. Shimoda, K., Kato, K., Aoki, K., Matsuda, T., Miyamoto, A., Shibamori, M., Yamashita, M., Numata, A., Takase, K., Kobayashi, S., Shibata, S., Asano, Y., Gondo, H., Sekiguchi, K., Nakayama, K., Nakayama, T., Okamura, T., Okamura, S., Niho, Y., Nakayama, K., Tyk2 plays a restricted role in IFN alpha signaling, although it is required for IL-12-mediated T cell function. Immunity 13 (2000), 561–571.
309. Siegel, A.M., Heimall, J., Freeman, A.F., Hsu, A.P., Brittain, E., Brenchley, J.M., Douek, D.C., Fahle, G.H., Cohen, J.I., Holland, S.M., Milner, J.D., A critical role for STAT3 transcription factor signaling in the development and maintenance of human T cell memory. Immunity 35 (2011), 806–818.
310. Simeone-Penney, M.C., Severgnini, M., Tu, P., Homer, R.J., Mariani, T.J., Cohn, L., Simon, A.R., Airway epithelial STAT3 is required for allergic inflammation in a murine model of asthma. J. Immunol. 178 (2007), 6191–6199.
311. Simpson, S.J., Shah, S., Comiskey, M., De Jong, Y.P., Wang, B., Mizoguchi, E., Bhan, A.K., Terhorst, C., T cell-mediated pathology in two models of experimental colitis depends predominantly on the interleukin 12/Signal transducer and activator of transcription (Stat)-4 pathway, but is not conditional on interferon gamma expression by T cells. J. Exp. Med. 187 (1998), 1225–1234.
312. Skapenko, A., Wendler, J., Lipsky, P.E., Kalden, J.R., Schulze-Koops, H., Altered memory T cell differentiation in patients with early rheumatoid arthritis. J. Immunol. 163 (1999), 491–499.
313. Sriram, K., Benkovic, S.A., Hebert, M.A., Miller, D.B., O'Callaghan, J.P., Induction of gp130-related cytokines and activation of JAK2/STAT3 pathway in astrocytes precedes up-regulation of glial fibrillary acidic protein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of neurodegeneration: key signaling pathway for astrogliosis in vivo?. J. Biol. Chem. 279 (2004), 19936–19947.
314. Staudt, V., Bothur, E., Klein, M., LINGNAU, K., Reuter, S., Grebe, N., Gerlitzki, B., Hoffmann, M., Ulges, A., Taube, C., Dehzad, N., Becker, M., Stassen, M., Steinborn, A., Lohoff, M., Schild, H., Schmitt, E., Bopp, T., Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 33 (2010), 192–202.
315. Stokes, K., Lamarche, N.M., Islam, N., Wood, A., Huang, W., August, A., Cutting edge: STAT6 signaling in eosinophils is necessary for development of allergic airway inflammation. J. Immunol. 194 (2015), 2477–2481.
316. Stout, B.A., Melendez, K., Seagrave, J., Holtzman, M.J., Wilson, B., Xiang, J., Tesfaigzi, Y., STAT1 activation causes translocation of Bax to the endoplasmic reticulum during the resolution of airway mucous cell hyperplasia by IFN-gamma. J. Immunol. 178 (2007), 8107–8116.
317. Stritesky, G.L., Yeh, N., Kaplan, M.H., IL-23 promotes maintenance but not commitment to the Th17 lineage. J. Immunol. 181 (2008), 5948–5955.
318. Stritesky, G.L., Muthukrishnan, R., Sehra, S., Goswami, R., Pham, D., Travers, J., Nguyen, E.T., Levy, D.E., Kaplan, M.H., The transcription factor STAT3 is required for T helper 2 cell development. Immunity 34 (2011), 39–49.
319. Sugimoto, K., Ogawa, A., Mizoguchi, E., Shimomura, Y., Andoh, A., Bhan, A.K., Blumberg, R.S., Xavier, R.J., Mizoguchi, A., IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J. Clin. Invest. 118 (2008), 534–544.
320. Summers, S.A., Phoon, R.K., Odobasic, D., Dewage, L., Kitching, A.R., Holdsworth, S.R., Signal transducer and activation of transcription 6 (STAT6) regulates T helper type 1 (Th1) and Th17 nephritogenic immunity in experimental crescentic glomerulonephritis. Clin. Exp. Immunol. 166 (2011), 227–234.
321. Sutherland, A.P., Joller, N., Michaud, M., Liu, S.M., Kuchroo, V.K., Grusby, M.J., IL-21 promotes CD8 + CTL activity via the transcription factor T-bet. J. Immunol. 190 (2013), 3977–3984.
322. Suto, A., Wurster, A.L., Reiner, S.L., Grusby, M.J., IL-21 inhibits IFN-gamma production in developing Th1 cells through the repression of eomesodermin expression. J. Immunol. 177 (2006), 3721–3727.
323. Suto, A., Kashiwakuma, D., Kagami, S., Hirose, K., Watanabe, N., Yokote, K., Saito, Y., Nakayama, T., Grusby, M.J., Iwamoto, I., Nakajima, H., Development and characterization of IL-21-producing CD4 + T cells. J. Exp. Med. 205 (2008), 1369–1379.
324. Suzuki, Y., Orellana, M.A., Schreiber, R.D., Remington, J.S., Interferon-gamma: the major mediator of resistance against Toxoplasma gondii. Science 240 (1988), 516–518.
325. Swain, S.L., Weinberg, A.D., English, M., Huston, G., IL-4 directs the development of Th2-like helper effectors. J. Immunol. 145 (1990), 3796–3806.
326. Tachdjian, R., Mathias, C., Al Khatib, S., Bryce, P.J., Kim, H.S., Blaeser, F., O'connor, B.D., Rzymkiewicz, D., Chen, A., Holtzman, M.J., Hershey, G.K., Garn, H., Harb, H., Renz, H., Oettgen, H.C., Chatila, T.A., Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma. J. Exp. Med. 206 (2009), 2191–2204.
327. Takahashi, T., Tagami, T., Yamazaki, S., Uede, T., Shimizu, J., Sakaguchi, N., Mak, T.W., Sakaguchi, S., Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 192 (2000), 303–310.
328. Takaki, H., Ichiyama, K., Koga, K., Chinen, T., Takaesu, G., Sugiyama, Y., Kato, S., Yoshimura, A., Kobayashi, T., STAT6 inhibits TGF-beta1-mediated Foxp3 induction through direct binding to the Foxp3 promoter, which is reverted by retinoic acid receptor. J. Biol. Chem. 283 (2008), 14955–14962.
329. Takatori, H., Nakajima, H., Hirose, K., Kagami, S., Tamachi, T., Suto, A., Suzuki, K., Saito, Y., Iwamoto, I., Indispensable role of Stat5a in Stat6-independent Th2 cell differentiation and allergic airway inflammation. J. Immunol. 174 (2005), 3734–3740.
330. Takeda, K., Tanaka, T., Shi, W., Matsumoto, M., Minami, M., Kashiwamura, S., Nakanishi, K., Yoshida, N., Kishimoto, T., Akira, S., Essential role of Stat6 in IL-4 signalling. Nature 380 (1996), 627–630.
331. Takeda, K., Clausen, B.E., Kaisho, T., Tsujimura, T., Terada, N., Forster, I., Akira, S., Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10 (1999), 39–49.
332. Tan, C., Aziz, M.K., Lovaas, J.D., Vistica, B.P., Shi, G., Wawrousek, E.F., Gery, I., Antigen-specific Th9 cells exhibit uniqueness in their kinetics of cytokine production and short retention at the inflammatory site. J. Immunol. 185 (2010), 6795–6801.
333. Tanaka, Y., Recent progress and perspective in JAK inhibitors for rheumatoid arthritis: from bench to bedside. J. Biochem. 158 (2015), 173–179.
334. Tanaka, Y., Emoto, K., Cai, Z., Aoki, T., Schlichting, D., Rooney, T., Macias, W., Efficacy and safety of baricitinib in Japanese patients with active rheumatoid arthritis receiving background methotrexate therapy: a 12-week, double-blind, randomized placebo-controlled study. J. Rheumatol. 43 (2016), 504–511.
335. Tekkanat, K.K., Maassab, H.F., Cho, D.S., Lai, J.J., John, A., Berlin, A., Kaplan, M.H., Lukacs, N.W., IL-13-induced airway hyperreactivity during respiratory syncytial virus infection is STAT6 dependent. J. Immunol. 166 (2001), 3542–3548.
336. Thierfelder, W.E., Van Deursen, J.M., Yamamoto, K., Tripp, R.A., Sarawar, S.R., Carson, R.T., Sangster, M.Y., Vignali, D.A., Doherty, P.C., Grosveld, G.C., Ihle, J.N., Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 382 (1996), 171–174.
337. Thieu, V.T., Yu, Q., Chang, H.C., Yeh, N., Nguyen, E.T., Sehra, S., Kaplan, M.H., Signal transducer and activator of transcription 4 is required for the transcription factor T-bet to promote T helper 1 cell-fate determination. Immunity 29 (2008), 679–690.
338. Tomkinson, A., Kanehiro, A., Rabinovitch, N., Joetham, A., Cieslewicz, G., Gelfand, E.W., The failure of STAT6-deficient mice to develop airway eosinophilia and airway hyperresponsiveness is overcome by interleukin-5. Am. J. Respir. Crit. Care Med. 160 (1999), 1283–1291.
339. Tosiek, M.J., Fiette, L., El Daker, S., Eberl, G., Freitas, A.A., IL-15-dependent balance between Foxp3 and RORgammat expression impacts inflammatory bowel disease. Nat. Commun., 7, 2016, 10888.
340. Trinchieri, G., Pflanz, S., Kastelein, R.A., The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. Immunity 19 (2003), 641–644.
341. Ubel, C., Graser, A., Koch, S., Rieker, R.J., Lehr, H.A., Muller, M., Finotto, S., Role of Tyk-2 in Th9 and Th17 cells in allergic asthma. Sci. Rep., 4, 2014, 5865.
342. Urban, J.F. Jr., Noben-Trauth, N., Donaldson, D.D., Madden, K.B., Morris, S.C., Collins, M., Finkelman, F.D., IL-13, IL-4Ralpha, and Stat6 are required for the expulsion of the gastrointestinal nematode parasite Nippostrongylus brasiliensis. Immunity 8 (1998), 255–264.
343. Uzel, G., Sampaio, E.P., Lawrence, M.G., Hsu, A.P., Hackett, M., Dorsey, M.J., Noel, R.J., Verbsky, J.W., Freeman, A.F., Janssen, E., Bonilla, F.A., Pechacek, J., Chandrasekaran, P., Browne, S.K., Agharahimi, A., Gharib, A.M., Mannurita, S.C., Yim, J.J., Gambineri, E., Torgerson, T., Tran, D.Q., Milner, J.D., Holland, S.M., Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome. J. Allergy Clin. Immunol. 131 (2013), 1611–1623.
344. Van De Veerdonk, F.L., Plantinga, T.S., Hoischen, A., Smeekens, S.P., Joosten, L.A., Gilissen, C., Arts, P., Rosentul, D.C., Carmichael, A.J., Smits-Van der Graaf, C.A., Kullberg, B.J., Van Der Meer, J.W., Lilic, D., Veltman, J.A., Netea, M.G., STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N. Engl. J. Med. 365 (2011), 54–61.
345. Van Der Fits, L., Van Kester, M.S., Qin, Y., Out-Luiting, J.J., Smit, F., Zoutman, W.H., Willemze, R., Tensen, C.P., Vermeer, M.H., MicroRNA-21 expression in CD4 + T cells is regulated by STAT3 and is pathologically involved in Sezary syndrome. J. Invest. Dermatol. 131 (2011), 762–768.
346. Van Der Heijde, D., Tanaka, Y., Fleischmann, R., Keystone, E., Kremer, J., Zerbini, C., Cardiel, M.H., Cohen, S., Nash, P., Song, Y.W., Tegzova, D., Wyman, B.T., Gruben, D., Benda, B., Wallenstein, G., Krishnaswami, S., Zwillich, S.H., Bradley, J.D., Connell, C.A., Investigators, O.S., Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum. 65 (2013), 559–570.
347. Van Panhuys, N., Tang, S.C., Prout, M., Camberis, M., Scarlett, D., Roberts, J., Hu-Li, J., Paul, W.E., Le Gros, G., In vivo studies fail to reveal a role for IL-4 or STAT6 signaling in Th2 lymphocyte differentiation. Proc. Natl. Acad. Sci. U.S.A. 105 (2008), 12423–12428.
348. Van Vollenhoven, R.F., Fleischmann, R., Cohen, S., Lee, E.B., Garcia Meijide, J.A., Wagner, S., Forejtova, S., Zwillich, S.H., Gruben, D., Koncz, T., Wallenstein, G.V., Krishnaswami, S., Bradley, J.D., Wilkinson, B., Oral Standard Investigators, Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N. Engl. J. Med. 367 (2012), 508–519.
349. Vegran, F., Berger, H., Boidot, R., Mignot, G., Bruchard, M., Dosset, M., Chalmin, F., Rebe, C., Derangere, V., Ryffel, B., Kato, M., Prevost-Blondel, A., Ghiringhelli, F., Apetoh, L., The transcription factor IRF1 dictates the IL-21-dependent anticancer functions of TH9 cells. Nat. Immunol. 15 (2014), 758–766.
350. Veldhoen, M., Hocking, R.J., Atkins, C.J., Locksley, R.M., Stockinger, B., TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24 (2006), 179–189.
351. Veldhoen, M., Hocking, R.J., Flavell, R.A., Stockinger, B., Signals mediated by transforming growth factor-beta initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat. Immunol. 7 (2006), 1151–1156.
352. Veldhoen, M., Uyttenhove, C., Van Snick, J., Helmby, H., Westendorf, A., Buer, J., Martin, B., Wilhelm, C., Stockinger, B., Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat. Immunol. 9 (2008), 1341–1346.
353. Villarino, A.V., Gallo, E., Abbas, A.K., STAT1-activating cytokines limit Th17 responses through both T-bet-dependent and -independent mechanisms. J. Immunol. 185 (2010), 6461–6471.
354. Vinkemeier, U., Moarefi, I., Darnell, J.E. Jr., Kuriyan, J., Structure of the amino-terminal protein interaction domain of STAT-4. Science 279 (1998), 1048–1052.
355. Visekruna, A., Ritter, J., Scholz, T., Campos, L., Guralnik, A., Poncette, L., Raifer, H., Hagner, S., Garn, H., Staudt, V., Bopp, T., Reuter, S., Taube, C., Loser, K., Huber, M., Tc9 cells, a new subset of CD8(+) T cells, support Th2-mediated airway inflammation. Eur. J. Immunol. 43 (2013), 606–618.
356. Vogelzang, A., Mcguire, H.M., Yu, D., Sprent, J., Mackay, C.R., King, C., A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity 29 (2008), 127–137.
357. Walker, J.G., Ahern, M.J., Coleman, M., Weedon, H., Papangelis, V., Beroukas, D., Roberts-Thomson, P.J., Smith, M.D., Expression of Jak3, STAT1, STAT4, and STAT6 in inflammatory arthritis: unique Jak3 and STAT4 expression in dendritic cells in seropositive rheumatoid arthritis. Ann. Rheum. Dis. 65 (2006), 149–156.
358. Walker, J.G., Ahern, M.J., Coleman, M., Weedon, H., Papangelis, V., Beroukas, D., Roberts-Thomson, P.J., Smith, M.D., Characterisation of a dendritic cell subset in synovial tissue which strongly expresses Jak/STAT transcription factors from patients with rheumatoid arthritis. Ann. Rheum. Dis. 66 (2007), 992–999.
359. Wang, Y., Evans, J.T., Rodriguez, F., Fields, P., Mueller, C., Chitnis, T., Khoury, S.J., Bynoe, M.S., A tale of two STAT6 knock out mice in the induction of experimental autoimmune encephalomyelitis. J. Neuroimmunol. 206 (2009), 76–85.
360. Ware, C.F., Network communications: lymphotoxins, LIGHT, and TNF. Annu. Rev. Immunol. 23 (2005), 787–819.
361. Weber, M.S., Prod'homme, T., Youssef, S., Dunn, S.E., Steinman, L., Zamvil, S.S., Neither T-helper type 2 nor Foxp3 + regulatory T cells are necessary for therapeutic benefit of atorvastatin in treatment of central nervous system autoimmunity. J. Neuroinflammation, 11, 2014, 29.
362. Wei, L., Vahedi, G., Sun, H.W., Watford, W.T., Takatori, H., Ramos, H.L., Takahashi, H., Liang, J., Gutierrez-Cruz, G., Zang, C., Peng, W., O'Shea, J.J., Kanno, Y., Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation. Immunity 32 (2010), 840–851.
363. Wenta, N., Strauss, H., Meyer, S., Vinkemeier, U., Tyrosine phosphorylation regulates the partitioning of STAT1 between different dimer conformations. Proc. Natl. Acad. Sci. U.S.A. 105 (2008), 9238–9243.
364. Wirtz, S., Finotto, S., Kanzler, S., Lohse, A.W., Blessing, M., Lehr, H.A., Galle, P.R., Neurath, M.F., Cutting edge: chronic intestinal inflammation in STAT-4 transgenic mice: characterization of disease and adoptive transfer by TNF- plus IFN-gamma-producing CD4 + T cells that respond to bacterial antigens. J. Immunol. 162 (1999), 1884–1888.
365. Witthuhn, B.A., Quelle, F.W., Silvennoinen, O., Yi, T., Tang, B., Miura, O., Ihle, J.N., JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell 74 (1993), 227–236.
366. Wjst, M., Lichtner, P., Meitinger, T., Grimbacher, B., STAT3 single-nucleotide polymorphisms and STAT3 mutations associated with hyper-IgE syndrome are not responsible for increased serum IgE serum levels in asthma families. Eur. J. Hum. Genet. 17 (2009), 352–356.
367. Wu, X., Pan, W., He, Y., Hsuchou, H., Kastin, A.J., Cerebral interleukin-15 shows upregulation and beneficial effects in experimental autoimmune encephalomyelitis. J. Neuroimmunol. 223 (2010), 65–72.
368. Wu, X., Guo, W., Wu, L., Gu, Y., Gu, L., Xu, S., Wu, X., Shen, Y., Ke, Y., Tan, R., Sun, Y., Xu, Q., Selective sequestration of STAT1 in the cytoplasm via phosphorylated SHP-2 ameliorates murine experimental colitis. J. Immunol. 189 (2012), 3497–3507.
369. Wu, H., Xu, L.L., Teuscher, P., Liu, H., Kaplan, M.H., Dent, A.L., An inhibitory role for the transcription factor Stat3 in controlling IL-4 and Bcl6 expression in follicular helper T cells. J. Immunol. 195 (2015), 2080–2089.
370. Wu, L., Zepp, J.A., Qian, W., Martin, B.N., Ouyang, W., Yin, W., Bunting, K.D., Aronica, M., Erzurum, S., Li, X., A novel IL-25 signaling pathway through STAT5. J. Immunol. 194 (2015), 4528–4534.
371. Wu, H., Chen, Y., Liu, H., Xu, L.L., Teuscher, P., Wang, S., Lu, S., Dent, A.L., Follicular regulatory T cells repress cytokine production by follicular helper T cells and optimize IgG responses in mice. Eur. J. Immunol. 46 (2016), 1152–1161.
372. Wu, H., Xie, M.M., Liu, H., Dent, A.L., Stat3 is important for follicular regulatory T cell differentiation. PLoS One, 11, 2016, e0155040.
373. Wurster, A.L., Rodgers, V.L., Satoskar, A.R., Whitters, M.J., Young, D.A., Collins, M., Grusby, M.J., Interleukin 21 is a T helper (Th) cell 2 cytokine that specifically inhibits the differentiation of naive Th cells into interferon gamma-producing Th1 cells. J. Exp. Med. 196 (2002), 969–977.
374. Wynn, T.A., IL-13 effector functions. Annu. Rev. Immunol. 21 (2003), 425–456.
375. Xia, B., Crusius, J.B., Wu, J., Zwiers, A., van Bodegraven, A.A., Pena, A.S., Signal transducer and activator of transcription 6 gene G2964A polymorphism and inflammatory bowel disease. Clin. Exp. Immunol. 131 (2003), 446–450.
376. Xu, L., Kitani, A., Stuelten, C., McGrady, G., Fuss, I., Strober, W., Positive and negative transcriptional regulation of the Foxp3 gene is mediated by access and binding of the Smad3 protein to enhancer I. Immunity 33 (2010), 313–325.
377. Xu, J., Yang, Y., Qiu, G., Lal, G., Yin, N., Wu, Z., Bromberg, J.S., Ding, Y., Stat4 is critical for the balance between Th17 cells and regulatory T cells in colitis. J. Immunol. 186 (2011), 6597–6606.
378. Yamaoka, K., Saharinen, P., Pesu, M., Holt, V.E. 3rd., Silvennoinen, O., O'Shea, J.J., The Janus kinases (Jaks). Genome Biol., 5, 2004, 253.
379. Yang, J., Murphy, T.L., Ouyang, W., Murphy, K.M., Induction of interferon-gamma production in Th1 CD4 + T cells: evidence for two distinct pathways for promoter activation. Eur. J. Immunol. 29 (1999), 548–555.
380. Yang, M., Hogan, S.P., Henry, P.J., Matthaei, K.I., McKenzie, A.N., Young, I.G., Rothenberg, M.E., Foster, P.S., Interleukin-13 mediates airways hyperreactivity through the IL-4 receptor-alpha chain and STAT-6 independently of IL-5 and eotaxin. Am. J. Respir. Cell Mol. Biol. 25 (2001), 522–530.
381. Yang, X.O., Panopoulos, A.D., Nurieva, R., Chang, S.H., Wang, D., Watowich, S.S., Dong, C., STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J. Biol. Chem. 282 (2007), 9358–9363.
382. Yang, X.O., Pappu, B.P., Nurieva, R., Akimzhanov, A., Kang, H.S., Chung, Y., Ma, L., Shah, B., Panopoulos, A.D., Schluns, K.S., Watowich, S.S., Tian, Q., Jetten, A.M., Dong, C., T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 28 (2008), 29–39.
383. Yang, E.J., Lee, J., Lee, S.Y., Kim, E.K., Moon, Y.M., Jung, Y.O., Park, S.H., Cho, M.L., EGCG attenuates autoimmune arthritis by inhibition of STAT3 and HIF-1alpha with Th17/Treg control. PLoS One, 9, 2014, e86062.
384. Yao, Z., Kanno, Y., Kerenyi, M., Stephens, G., Durant, L., Watford, W.T., Laurence, A., Robinson, G.W., Shevach, E.M., Moriggl, R., Hennighausen, L., Wu, C., O'Shea, J.J., Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 109 (2007), 4368–4375.
385. Yeh, N., Glosson, N.L., Wang, N., Guindon, L., McKinley, C., Hamada, H., Li, Q., Dutton, R.W., Shrikant, P., Zhou, B., Brutkiewicz, R.R., Blum, J.S., Kaplan, M.H., Tc17 cells are capable of mediating immunity to vaccinia virus by acquisition of a cytotoxic phenotype. J. Immunol. 185 (2010), 2089–2098.
386. Yen, H.R., Harris, T.J., Wada, S., Grosso, J.F., Getnet, D., Goldberg, M.V., Liang, K.L., Bruno, T.C., Pyle, K.J., Chan, S.L., Anders, R.A., Trimble, C.L., Adler, A.J., Lin, T.Y., Pardoll, D.M., Huang, C.T., Drake, C.G., Tc17 CD8 T cells: functional plasticity and subset diversity. J. Immunol. 183 (2009), 7161–7168.
387. Youssef, S., Stuve, O., Patarroyo, J.C., Ruiz, P.J., Radosevich, J.L., Hur, E.M., Bravo, M., Mitchell, D.J., Sobel, R.A., Steinman, L., Zamvil, S.S., The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420 (2002), 78–84.
388. Yu, C.R., Lee, Y.S., Mahdi, R.M., Surendran, N., Egwuagu, C.E., Therapeutic targeting of STAT3 (signal transducers and activators of transcription 3) pathway inhibits experimental autoimmune uveitis. PLoS One, 7, 2012, e29742.
389. Yu, C.R., Dambuza, I.M., Lee, Y.J., Frank, G.M., Egwuagu, C.E., STAT3 regulates proliferation and survival of CD8 + T cells: enhances effector responses to HSV-1 infection, and inhibits IL-10 + regulatory CD8 + T cells in autoimmune uveitis. Mediators Inflamm., 2013, 2013, 359674.
390. Yu, F., Sharma, S., Edwards, J., Feigenbaum, L., Zhu, J., Dynamic expression of transcription factors T-bet and GATA-3 by regulatory T cells maintains immunotolerance. Nat. Immunol. 16 (2015), 197–206.
391. Zhang, Z., Jones, S., Hagood, J.S., Fuentes, N.L., Fuller, G.M., STAT3 acts as a co-activator of glucocorticoid receptor signaling. J. Biol. Chem. 272 (1997), 30607–30610.
392. Zhang, G.X., Gran, B., Yu, S., Li, J., Siglienti, I., Chen, X., Kamoun, M., Rostami, A., Induction of experimental autoimmune encephalomyelitis in IL-12 receptor-beta 2-deficient mice: IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the central nervous system. J. Immunol. 170 (2003), 2153–2160.
393. Zhao, Y., Liu, X., Liu, X., Su, Y., Li, Y., Zhang, X., Zhu, L., Wang, S., Wang, T., Jiang, Q., Liu, X., Li, X., Huang, C., Jia, R., Lu, X., Guo, J., Li, Z., Association of STAT4 gene polymorphism with increased susceptibility of rheumatoid arthritis in a northern Chinese Han subpopulation. Int. J. Rheum. Dis. 16 (2013), 178–184.
394. Zhou, L., Ivanov, I.I., Spolski, R., Min, R., Shenderov, K., Egawa, T., Levy, D.E., Leonard, W.J., Littman, D.R., IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat. Immunol. 8 (2007), 967–974.
395. Zhou, L., Kawate, T., Liu, X., Kim, Y.B., Zhao, Y., Feng, G., Banerji, J., Nash, H., Whitehurst, C., Jindal, S., Siddiqui, A., Seed, B., Wolfe, J.L., STAT6 phosphorylation inhibitors block eotaxin-3 secretion in bronchial epithelial cells. Bioorg. Med. Chem. 20 (2012), 750–758.
396. Zhu, J., Paul, W.E., CD4 T cells: fates, functions, and faults. Blood 112 (2008), 1557–1569.
397. Zhu, J., Paul, W.E., Peripheral CD4 + T-cell differentiation regulated by networks of cytokines and transcription factors. Immunol. Rev. 238 (2010), 247–262.
398. Zhu, J., Guo, L., Min, B., Watson, C.J., Hu-Li, J., Young, H.A., Tsichlis, P.N., Paul, W.E., Growth factor independent-1 induced by IL-4 regulates Th2 cell proliferation. Immunity 16 (2002), 733–744.
399. Zhu, J., Cote-Sierra, J., Guo, L., Paul, W.E., Stat5 activation plays a critical role in Th2 differentiation. Immunity 19 (2003), 739–748.
400. Zhu, J., Yamane, H., Paul, W.E., Differentiation of effector CD4 T cell populations (*). Annu. Rev. Immunol. 28 (2010), 445–489.