Type I IFN induces binding of STAT1 to BCL6: Divergent roles of stat family transcription factors in the T follicular helper cell genetic program

Journal of Immunology

Volumn 192, Issue 5, 2014, Pages 2156-2166

  Nakayamada, Shingo ^a   Poholek, Amanda C ^a   Lu, Kristina T ^b   Takahashi, Hayato ^a   Kato, Masanari ^a   Iwata, Shigeru ^a   Hirahara, Kiyoshi ^a   Cannons, Jennifer L ^b   Schwartzberg, Pamela L ^b   Vahedi, Golnaz ^a   Sun, Hong Wei ^a   Kanno, Yuka ^a   O'Shea, John J ^a  

^a NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES   (United States)

^b NATIONAL HUMAN GENOME RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA INTERFERON; BETA INTERFERON; CHEMOKINE RECEPTOR CXCR5; INTERLEUKIN 21; PROGRAMMED DEATH 1 RECEPTOR; PROTEIN BCL 6; STAT1 PROTEIN;

ANIMAL CELL; ARTICLE; BCL6 GENE; CELL SURFACE; CXCR5 GENE; CYTOKINE PRODUCTION; GENE EXPRESSION; GENE LOCUS; GENETIC ANALYSIS; IMMUNE RESPONSE; INTERFERON ALPHA GENE; INTERFERON BETA GENE; LYMPHOCYTE DIFFERENTIATION; MOUSE; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN EXPRESSION; STAT1 GENE; TH1 CELL;

ANIMALS; CYTOKINES; DNA-BINDING PROTEINS; GENE EXPRESSION REGULATION; INTERFERON TYPE I; MICE; MICE, KNOCKOUT; PROGRAMMED CELL DEATH 1 RECEPTOR; QUANTITATIVE TRAIT LOCI; RECEPTORS, CXCR5; STAT1 TRANSCRIPTION FACTOR; T-LYMPHOCYTES, HELPER-INDUCER;

EID: 84896532800     PISSN: 00221767     EISSN: 15506606     Source Type: Journal    
DOI: 10.4049/jimmunol.1300675     Document Type: Article

References (90)

1. Abbas, A. K., K. M. Murphy, and A. Sher. 1996. Functional diversity of helper T lymphocytes. Nature 383: 787-793.
2. Miller, J. F., P. M. De Burgh, and G. A. Grant. 1965. Thymus and the production of antibody-plaque-forming cells. Nature 208: 1332-1334.
3. Friedman, H. 1965. Absence of antibody plaque forming cells in spleens of thymectomized mice immunized with sheep erythrocytes. Proc. Soc. Exp. Biol. Med. 118: 1176-1180.
4. Crotty, S. 2011. Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 29: 621-663.
5. Breitfeld, D., L. Ohl, E. Kremmer, J. Ellwart, F. Sallusto, M. Lipp, and R. Förster. 2000. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J. Exp. Med. 192: 1545-1552.
6. Schaerli, P., K. Willimann, A. B. Lang, M. Lipp, P. Loetscher, and B. Moser. 2000. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J. Exp. Med. 192: 1553-1562.
7. Kim, C. H., L. S. Rott, I. Clark-Lewis, D. J. Campbell, L. Wu, and E. C. Butcher. 2001. Subspecialization of CXCR5+ T cells: B helper activity is focused in a germinal center-localized subset of CXCR5+ T cells. J. Exp. Med. 193: 1373-1381.
8. Haynes, N. M., C. D. Allen, R. Lesley, K. M. Ansel, N. Killeen, and J. G. Cyster. 2007. Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1high germinal center-Associated subpopulation. J. Immunol. 179: 5099-5108.
9. Hutloff, A., A. M. Dittrich, K. C. Beier, B. Eljaschewitsch, R. Kraft, I. Anagnostopoulos, and R. A. Kroczek. 1999. ICOS is an inducible T-cell costimulator structurally and functionally related to CD28. Nature 397: 263-266.
10. Vinuesa, C. G., M. C. Cook, C. Angelucci, V. Athanasopoulos, L. Rui, K. M. Hill, D. Yu, H. Domaschenz, B. Whittle, T. Lambe, et al. 2005. A RINGtype ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435: 452-458.
11. King, I. L., and M. Mohrs. 2009. IL-4-producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells. J. Exp. Med. 206: 1001-1007.
12. Reinhardt, R. L., H. E. Liang, and R. M. Locksley. 2009. Cytokine-secreting follicular T cells shape the antibody repertoire. Nat. Immunol. 10: 385-393.
13. Chtanova, T., S. G. Tangye, R. Newton, N. Frank, M. R. Hodge, M. S. Rolph, and C. R. Mackay. 2004. 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: 68-78.
14. Glatman Zaretsky, A., J. J. Taylor, I. L. King, F. A. Marshall, M. Mohrs, and E. J. Pearce. 2009. T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J. Exp. Med. 206: 991-999.
15. Yusuf, I., R. Kageyama, L. Monticelli, R. J. Johnston, D. Ditoro, K. Hansen, B. Barnett, and S. Crotty. 2010. Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150). J. Immunol. 185: 190-202.
16. Moser, B., and L. Ebert. 2003. Lymphocyte traffic control by chemokines: follicular B helper T cells. Immunol. Lett. 85: 105-112.
17. Qi, H., J. L. Cannons, F. Klauschen, P. L. Schwartzberg, and R. N. Germain. 2008. SAP-controlled T-B cell interactions underlie germinal centre formation. Nature 455: 764-769.
18. Cannons, J. L., S. G. Tangye, and P. L. Schwartzberg. 2011. SLAM family receptors and SAP adaptors in immunity. Annu. Rev. Immunol. 29: 665-705.
19. Cannons, J. L., H. Qi, K. T. Lu, M. Dutta, J. Gomez-Rodriguez, J. Cheng, E. K.Wakeland, R. N. Germain, and P. L. Schwartzberg. 2010. Optimal germinal center responses require a multistage T cell:B cell adhesion process involving integrins, SLAM-Associated protein, and CD84. Immunity 32: 253-265.
20. Cannons, J. L., L. J. Yu, D. Jankovic, S. Crotty, R. Horai, M. Kirby, S. Anderson, A. W. Cheever, A. Sher, and P. L. Schwartzberg. 2006. SAP regulates T cellmediated help for humoral immunity by a mechanism distinct from cytokine regulation. J. Exp. Med. 203: 1551-1565.
21. Crotty, S., E. N. Kersh, J. Cannons, P. L. Schwartzberg, and R. Ahmed. 2003. SAP is required for generating long-term humoral immunity. Nature 421: 282-287.
22. Dong, C., U. A. Temann, and R. A. Flavell. 2001. Cutting edge: critical role of inducible costimulator in germinal center reactions. J. Immunol. 166: 3659-3662.
23. McAdam, A. J., R. J. Greenwald, M. A. Levin, T. Chernova, N. Malenkovich, V. Ling, G. J. Freeman, and A. H. Sharpe. 2001. ICOS is critical for CD40-mediated antibody class switching. Nature 409: 102-105.
24. Tafuri, A., A. Shahinian, F. Bladt, S. K. Yoshinaga, M. Jordana, A. Wakeham, L. M. Boucher, D. Bouchard, V. S. Chan, G. Duncan, et al. 2001. ICOS is essential for effective T-helper-cell responses. Nature 409: 105-109.
25. Renshaw, B. R., W. C. Fanslow, III, R. J. Armitage, K. A. Campbell, D. Liggitt, B. Wright, B. L. Davison, and C. R. Maliszewski. 1994. Humoral immune responses in CD40 ligand-deficient mice. J. Exp. Med. 180: 1889-1900.
26. Grewal, I. S., J. Xu, and R. A. Flavell. 1995. Impairment of antigen-specific Tcell priming in mice lacking CD40 ligand. Nature 378: 617-620.
27. Ozaki, K., R. Spolski, C. G. Feng, C. F. Qi, J. Cheng, A. Sher, H. C. Morse, III, C. Liu, P. L. Schwartzberg, and W. J. Leonard. 2002. A critical role for IL-21 in regulating immunoglobulin production. Science 298: 1630-1634.
28. Johnston, R. J., A. C. Poholek, D. DiToro, I. Yusuf, D. Eto, B. Barnett, A. L. Dent, J. Craft, and S. Crotty. 2009. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325: 1006-1010.
29. Yu, D., S. Rao, L. M. Tsai, S. K. Lee, Y. He, E. L. Sutcliffe, M. Srivastava, M. Linterman, L. Zheng, N. Simpson, et al. 2009. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31: 457-468.
30. Nurieva, R. I., Y. Chung, G. J. Martinez, X. O. Yang, S. Tanaka, T. D. Matskevitch, Y. H. Wang, and C. Dong. 2009. Bcl6 mediates the development of T follicular helper cells. Science 325: 1001-1005.
31. Kusam, S., L. M. Toney, H. Sato, and A. L. Dent. 2003. Inhibition of Th2 differentiation and GATA-3 expression by BCL-6. J. Immunol. 170: 2435-2441.
32. Lu, K. T., Y. Kanno, J. L. Cannons, R. Handon, P. Bible, A. G. Elkahloun, S. M. Anderson, L. Wei, H. Sun, J. J. O'Shea, and P. L. Schwartzberg. 2011. Functional and epigenetic studies reveal multistep differentiation and plasticity of in vitro-generated and in vivo-derived follicular T helper cells. Immunity 35: 622-632.
33. Eddahri, F., S. Denanglaire, F. Bureau, R. Spolski, W. J. Leonard, O. Leo, and F. Andris. 2009. Interleukin-6/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities. Blood 113: 2426-2433.
34. Nurieva, R. I., Y. Chung, D. Hwang, X. O. Yang, H. S. Kang, L. Ma, Y. H. Wang, S. S. Watowich, A. M. Jetten, Q. Tian, and C. Dong. 2008. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29: 138-149.
35. Vogelzang, A., H. M. McGuire, D. Yu, J. Sprent, C. R. Mackay, and C. King. 2008. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity 29: 127-137.
36. Poholek, A. C., K. Hansen, S. G. Hernandez, D. Eto, A. Chandele, J. S. Weinstein, X. Dong, J. M. Odegard, S. M. Kaech, A. L. Dent, et al. 2010. In vivo regulation of Bcl6 and T follicular helper cell development. J. Immunol. 185: 313-326.
37. Eto, D., C. Lao, D. DiToro, B. Barnett, T. C. Escobar, R. Kageyama, I. Yusuf, and S. Crotty. 2011. 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: e17739.
38. Karnowski, A., S. Chevrier, G. T. Belz, A. Mount, D. Emslie, K. D'Costa, D. M. Tarlinton, A. Kallies, and L. M. Corcoran. 2012. B and T cells collaborate in antiviral responses via IL-6, IL-21, and transcriptional activator and coactivator, Oct2 and OBF-1. J. Exp. Med. 209: 2049-2064.
39. Zotos, D., J. M. Coquet, Y. Zhang, A. Light, K. D'Costa, A. Kallies, L. M. Corcoran, D. I. Godfrey, K. M. Toellner, M. J. Smyth, et al. 2010. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J. Exp. Med. 207: 365-378.
40. Linterman, M. A., L. Beaton, D. Yu, R. R. Ramiscal, M. Srivastava, J. J. Hogan, N. K. Verma, M. J. Smyth, R. J. Rigby, and C. G. Vinuesa. 2010. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J. Exp. Med. 207: 353-363.
41. Harker, J. A., G. M. Lewis, L. Mack, and E. I. Zuniga. 2011. Late interleukin-6 escalates T follicular helper cell responses and controls a chronic viral infection. Science 334: 825-829.
42. O'Shea, J. J., and R. Plenge. 2012. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 36: 542-550.
43. O'Shea, J. J., R. Lahesmaa, G. Vahedi, A. Laurence, and Y. Kanno. 2011. Genomic views of STAT function in CD4+ T helper cell differentiation. Nat. Rev. Immunol. 11: 239-250.
44. Zhong, Z., Z. Wen, and J. E. Darnell, Jr. 1994. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264: 95-98.
45. Asao, H., C. Okuyama, S. Kumaki, N. Ishii, S. Tsuchiya, D. Foster, and K. Sugamura. 2001. Cutting edge: the common g-chain is an indispensable subunit of the IL-21 receptor complex. J. Immunol. 167: 1-5.
46. Ma, C. S., D. T. Avery, A. Chan, M. Batten, J. Bustamante, S. Boisson-Dupuis, P. D. Arkwright, A. Y. Kreins, D. Averbuch, D. Engelhard, et al. 2012. Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood 119: 3997-4008.
47. Schmitt, N., R. Morita, L. Bourdery, S. E. Bentebibel, S. M. Zurawski, J. Banchereau, and H. Ueno. 2009. Human dendritic cells induce the differentiation of interleukin-21-producing T follicular helper-like cells through interleukin-12. Immunity 31: 158-169.
48. Schmitt, N., J. Bustamante, L. Bourdery, S. E. Bentebibel, S. Boisson-Dupuis, F. Hamlin, M. V. Tran, D. Blankenship, V. Pascual, D. A. Savino, et al. 2013. IL-12 receptor b1 deficiency alters in vivo T follicular helper cell response in humans. Blood 121: 3375-3385.
49. Nakayamada, S., Y. Kanno, H. Takahashi, D. Jankovic, K. T. Lu, T. A. Johnson, H. W. Sun, G. Vahedi, O. Hakim, R. Handon, et al. 2011. Early Th1 cell differentiation is marked by a Tfh cell-like transition. Immunity 35: 919-931.
50. Oestreich, K. J., S. E. Mohn, and A. S. Weinmann. 2012. Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile. Nat. Immunol. 13: 405-411.
51. Johnston, R. J., Y. S. Choi, J. A. Diamond, J. A. Yang, and S. Crotty. 2012. STAT5 is a potent negative regulator of TFH cell differentiation. J. Exp. Med. 209: 243-250.
52. Nurieva, R. I., A. Podd, Y. Chen, A. M. Alekseev, M. Yu, X. Qi, H. Huang, R. Wen, J. Wang, H. S. Li, et al. 2012. STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function. J. Biol. Chem. 287: 11234-11239.
53. Ballesteros-Tato, A., B. León, B. A. Graf, A. Moquin, P. S. Adams, F. E. Lund, and T. D. Randall. 2012. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 36: 847-856.
54. Huber, J. P., and J. D. Farrar. 2011. Regulation of effector and memory T-cell functions by type I interferon. Immunology 132: 466-474.
55. Odorizzi, P. M., and E. J. Wherry. 2013. Immunology: an interferon paradox. Science 340: 155-156.
56. Teijaro, J. R., C. Ng, A. M. Lee, B. M. Sullivan, K. C. Sheehan, M. Welch, R. D. Schreiber, J. C. De la Torre, and M. B. Oldstone. 2013. Persistent LCMV infection is controlled by blockade of type I interferon signaling. Science 340: 207-211.
57. Wilson, E. B., D. H. Yamada, H. Elsaesser, J. Herskovitz, J. Deng, G. Cheng, B. J. Aronow, C. L. Karp, and D. G. Brooks. 2013. Blockade of chronic type I interferon signaling to control persistent LCMV infection. Science 340: 202-207.
58. Cho, S. S., C. M. Bacon, C. Sudarshan, R. C. Rees, D. Finbloom, R. Pine, and J. J. O'Shea. 1996. Activation of STAT4 by IL-12 and IFN-A: evidence for the involvement of ligand-induced tyrosine and serine phosphorylation. J. Immunol. 157: 4781-4789.
59. Farrar, J. D., J. D. Smith, T. L. Murphy, and K. M. Murphy. 2000. Recruitment of Stat4 to the human interferon-A/b receptor requires activated Stat2. J. Biol. Chem. 275: 2693-2697.
60. Berenson, L. S., J. D. Farrar, T. L. Murphy, and K. M. Murphy. 2004. Frontline: absence of functional STAT4 activation despite detectable tyrosine phosphorylation induced by murine IFN-A. Eur. J. Immunol. 34: 2365-2374.
61. Havenar-Daughton, C., G. A. Kolumam, and K. Murali-Krishna. 2006. Cutting edge: the direct action of type I IFN on CD4 T cells is critical for sustaining clonal expansion in response to a viral but not a bacterial infection. J. Immunol. 176: 3315-3319.
62. Way, S. S., C. Havenar-Daughton, G. A. Kolumam, N. N. Orgun, and K. Murali-Krishna. 2007. IL-12 and type-I IFN synergize for IFN-g production by CD4 T cells, whereas neither are required for IFN-g production by CD8 T cells after Listeria monocytogenes infection. J. Immunol. 178: 4498-4505.
63. Ramos, H. J., A. M. Davis, T. C. George, and J. D. Farrar. 2007. IFN-A is not sufficient to drive Th1 development due to lack of stable T-bet expression. J. Immunol. 179: 3792-3803.
64. Cucak, H., U. Yrlid, B. Reizis, U. Kalinke, and B. Johansson-Lindbom. 2009. Type I interferon signaling in dendritic cells stimulates the development of lymph-node-resident T follicular helper cells. Immunity 31: 491-501.
65. Le Bon, A., G. Schiavoni, G. D'Agostino, I. Gresser, F. Belardelli, and D. F. Tough. 2001. Type i interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo. Immunity 14: 461-470.
66. Durbin, J. E., R. Hackenmiller, M. C. Simon, and D. E. Levy. 1996. Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell 84: 443-450.
67. Lee, C. K., R. Raz, R. Gimeno, R. Gertner, B. Wistinghausen, K. Takeshita, R. A. DePinho, and D. E. Levy. 2002. STAT3 is a negative regulator of granulopoiesis but is not required for G-CSF-dependent differentiation. Immunity 17: 63-72.
68. Suto, A., D. Kashiwakuma, S. Kagami, K. Hirose, N. Watanabe, K. Yokote, Y. Saito, T. Nakayama, M. J. Grusby, I. Iwamoto, and H. Nakajima. 2008. Development and characterization of IL-21-producing CD4+ T cells. J. Exp. Med. 205: 1369-1379.
69. Wei, L., G. Vahedi, H. W. Sun, W. T. Watford, H. Takatori, H. L. Ramos, H. Takahashi, J. Liang, G. Gutierrez-Cruz, C. Zang, et al. 2010. Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation. Immunity 32: 840-851.
70. Wei, G., L. Wei, J. Zhu, C. Zang, J. Hu-Li, Z. Yao, K. Cui, Y. Kanno, T. Y. Roh, W. T. Watford, et al. 2009. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30: 155-167.
71. Murphy, K. M., W. Ouyang, J. D. Farrar, J. Yang, S. Ranganath, H. Asnagli, M. Afkarian, and T. L. Murphy. 2000. Signaling and transcription in T helper development. Annu. Rev. Immunol. 18: 451-494.
72. Bauquet, A. T., H. Jin, A. M. Paterson, M. Mitsdoerffer, I. C. Ho, A. H. Sharpe, and V. K. Kuchroo. 2009. 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: 167-175.
73. Kwon, H., D. Thierry-Mieg, J. Thierry-Mieg, H. P. Kim, J. Oh, C. Tunyaplin, S. Carotta, C. E. Donovan, M. L. Goldman, P. Tailor, et al. 2009. Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors. Immunity 31: 941-952.
74. Betz, B. C., K. L. Jordan-Williams, C. Wang, S. G. Kang, J. Liao, M. R. Logan, C. H. Kim, and E. J. Taparowsky. 2010. Batf coordinates multiple aspects of B and T cell function required for normal antibody responses. J. Exp. Med. 207: 933-942.
75. Ise, W., M. Kohyama, B. U. Schraml, T. Zhang, B. Schwer, U. Basu, F. W. Alt, J. Tang, E. M. Oltz, T. L. Murphy, and K. M. Murphy. 2011. The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells. Nat. Immunol. 12: 536-543.
76. Good-Jacobson, K. L., C. G. Szumilas, L. Chen, A. H. Sharpe, M. M. Tomayko, and M. J. Shlomchik. 2010. PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells. Nat. Immunol. 11: 535-542.
77. Ansel, K. M., L. J. McHeyzer-Williams, V. N. Ngo, M. G. McHeyzer-Williams, and J. G. Cyster. 1999. In vivo-Activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines. J. Exp. Med. 190: 1123-1134.
78. Agata, Y., A. Kawasaki, H. Nishimura, Y. Ishida, T. Tsubata, H. Yagita, and T. Honjo. 1996. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int. Immunol. 8: 765-772.
79. Zhou, L., I. I. Ivanov, R. Spolski, R. Min, K. Shenderov, T. Egawa, D. E. Levy, W. J. Leonard, and D. R. Littman. 2007. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat. Immunol. 8: 967-974.
80. Deenick, E. K., A. Chan, C. S. Ma, D. Gatto, P. L. Schwartzberg, R. Brink, and S. G. Tangye. 2010. Follicular helper T cell differentiation requires continuous antigen presentation that is independent of unique B cell signaling. Immunity 33: 241-253.
81. Goenka, R., L. G. Barnett, J. S. Silver, P. J. O'Neill, C. A. Hunter, M. P. Cancro, and T. M. Laufer. 2011. Cutting edge: dendritic cell-restricted antigen presentation initiates the follicular helper T cell program but cannot complete ultimate effector differentiation. J. Immunol. 187: 1091-1095.
82. Szabo, S. J., A. S. Dighe, U. Gubler, and K. M. Murphy. 1997. Regulation of the interleukin (IL)-12R b2 subunit expression in developing T helper 1 (Th1) and Th2 cells. J. Exp. Med. 185: 817-824.
83. Visel, A., M. J. Blow, Z. Li, T. Zhang, J. A. Akiyama, A. Holt, I. Plajzer-Frick, M. Shoukry, C. Wright, F. Chen, et al. 2009. ChIP-seq accurately predicts tissuespecific activity of enhancers. Nature 457: 854-858.
84. Vahedi, G., H. Takahashi, S. Nakayamada, H. W. Sun, V. Sartorelli, Y. Kanno, and J. J. O'Shea. 2012. STATs shape the active enhancer landscape of T cell populations. Cell 151: 981-993.
85. Choi, Y. S., D. Eto, J. A. Yang, C. Lao, and S. Crotty. 2013. Cutting edge: STAT1 is required for IL-6-mediated Bcl6 induction for early follicular helper cell differentiation. J. Immunol. 190: 3049-3053.
86. Yang, X. P., K. Ghoreschi, S. M. Steward-Tharp, J. Rodriguez-Canales, J. Zhu, J. R. Grainger, K. Hirahara, H. W. Sun, L. Wei, G. Vahedi, et al. 2011. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat. Immunol. 12: 247-254.
87. Vahedi, G., A. C Poholek, T. W. Hand, A. Laurence, Y. Kanno, J. J. O'Shea, and K. Hirahara. 2013. Helper T-cell identity and evolution of differential transcriptomes and epigenomes. Immunol. Rev. 252: 24-40.
88. Liao, W., J. X. Lin, L. Wang, P. Li, and W. J. Leonard. 2011. Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages. Nat. Immunol. 12: 551-559.
89. Oestreich, K. J., and A. S. Weinmann. 2012. Master regulators or lineagespecifying? Changing views on CD4+ T cell transcription factors. Nat. Rev. Immunol. 12: 799-804.
90. Obermoser, G., and V. Pascual. 2010. The interferon-A signature of systemic lupus erythematosus. Lupus 19: 1012-1019.