Origin and functions of pro-inflammatory cytokine producing Foxp3+ regulatory T cells

Cytokine

Volumn 76, Issue 1, 2015, Pages 13-24

  Pandiyan, Pushpa ^a   Zhu, Jinfang ^b  

^a CASE WESTERN RESERVE UNIVERSITY   (United States)

^b NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES   (United States)

Author keywords

Cytokine; Foxp3; IL 17; Inflammation; Reprogramming; Suppression; Treg; Th17

Indexed keywords

CHEMOKINE RECEPTOR CXCR3; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; GAMMA INTERFERON; INTERFERON REGULATORY FACTOR 4; INTERLEUKIN 17; INTERLEUKIN 6; STAT3 PROTEIN; TRANSCRIPTION FACTOR FOXP3; TRANSCRIPTION FACTOR GATA 3; TRANSFORMING GROWTH FACTOR BETA RECEPTOR 1; CYTOKINE; FORKHEAD TRANSCRIPTION FACTOR; FOXP3 PROTEIN, HUMAN; IL10 PROTEIN, HUMAN; IL17A PROTEIN, HUMAN; INTERLEUKIN 10; INTERLEUKIN DERIVATIVE; INTERLEUKIN-35, HUMAN;

ALLERGY; ARTHRITIS; CYTOKINE PRODUCTION; FOXP3+ REGULATORY T LYMPHOCYTE; GRAFT VERSUS HOST REACTION; HUMAN; IMMUNE RESPONSE; IMMUNOMODULATION; INFECTION; INFLAMMATION; INFLAMMATORY BOWEL DISEASE; INSULIN DEPENDENT DIABETES MELLITUS; MULTIPLE SCLEROSIS; NEOPLASM; NONHUMAN; PERIODONTITIS; PRIORITY JOURNAL; PROTEIN EXPRESSION; PSORIASIS; REGULATORY MECHANISM; REGULATORY T LYMPHOCYTE; REVIEW; SIGNAL TRANSDUCTION; TH17 CELL; TH2 CELL; BIOSYNTHESIS; CELLULAR IMMUNITY; IMMUNOLOGY; PATHOLOGY;

CYTOKINES; FORKHEAD TRANSCRIPTION FACTORS; HUMANS; IMMUNITY, CELLULAR; INTERFERON-GAMMA; INTERLEUKIN-10; INTERLEUKIN-17; INTERLEUKINS; T-LYMPHOCYTES, REGULATORY; TH17 CELLS;

EID: 84941739398     PISSN: 10434666     EISSN: 10960023     Source Type: Journal    
DOI: 10.1016/j.cyto.2015.07.005     Document Type: Review

References (202)

1. Pandiyan P., Zheng L., Lenardo M.J. The molecular mechanisms of regulatory T cell immunosuppression. Front. Immunol. 2011, 2:60.
2. Rudensky A.Y., Campbell D.J. In vivo sites and cellular mechanisms of T reg cell-mediated suppression. J. Exp. Med. 2006, 203:489-492.
3. Brunstein C.G., Miller J.S., Cao Q., McKenna D.H., Hippen K.L., Curtsinger J., et al. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood 2011, 117:1061-1070.
4. Canavan J.B., Scotta C., Vossenkamper A., Goldberg R., Elder M.J., Shoval I., et al. Developing in vitro expanded CD45RA+ regulatory T cells as an adoptive cell therapy for Crohn's disease. Gut 2015.
5. Kasagi S., Zhang P., Che L., Abbatiello B., Maruyama T., Nakatsukasa H., et al. In vivo-generated antigen-specific regulatory T cells treat autoimmunity without compromising antibacterial immune response. Sci. Translat. Med. 2014, 6:241ra78.
6. Koreth J., Matsuoka K., Kim H.T., McDonough S.M., Bindra B., Alyea E.P., et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. New England J. Med. 2011, 365:2055-2066.
7. Singer B.D., King L.S., D'Alessio F.R. Regulatory T cells as immunotherapy. Front. Immunol. 2014, 5:46.
8. Beriou G., Costantino C.M., Ashley C.W., Yang L., Kuchroo V.K., Baecher-Allan C., et al. IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood 2009, 113:4240-4249.
9. Du R., Zhao H., Yan F., Li H. IL-17+Foxp3+ T cells: an intermediate differentiation stage between Th17 cells and regulatory T cells. J. Leukoc. Biol. 2014, 96:39-48.
10. Hovhannisyan Z., Treatman J., Littman D.R., Mayer L. Characterization of interleukin-17-producing regulatory T cells in inflamed intestinal mucosa from patients with inflammatory bowel diseases. Gastroenterology 2011, 140:957-965.
11. Voo K.S., Wang Y.H., Santori F.R., Boggiano C., Wang Y.H., Arima K., et al. Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc. Natl. Acad. Sci. U.S.A. 2009, 106:4793-4798.
12. Whibley N., Maccallum D.M., Vickers M.A., Zafreen S., Waldmann H., Hori S., et al. Expansion of Foxp3(+) T-cell populations by Candida albicans enhances both Th17-cell responses and fungal dissemination after intravenous challenge. Eur. J. Immunol. 2014, 44:1069-1083.
13. reg functional stability and its responsiveness to the microenvironment. Immunol. Rev. 2014, 259:115-139.
14. reg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditions. Eur. J. Immunol. 2009, 39:948-955.
15. Pesenacker A.M., Broady R., Levings M.K. Control of tissue-localized immune responses by human regulatory T cells. Eur. J. Immunol. 2014.
16. Takahashi R., Yoshimura A. SOCS1 and regulation of regulatory T cells plasticity. J. Immunol. Res. 2014, 2014:943149.
17. Tsuji M., Komatsu N., Kawamoto S., Suzuki K., Kanagawa O., Honjo T., et al. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches. Science 2009, 323:1488-1492.
18. Zhou X., Bailey-Bucktrout S., Jeker L.T., Bluestone J.A. Plasticity of CD4(+) FoxP3(+) T cells. Curr. Opin. Immunol. 2009, 21:281-285.
19. Stock P., Akbari O., Berry G., Freeman G.J., Dekruyff R.H., Umetsu D.T. Induction of T helper type 1-like regulatory cells that express Foxp3 and protect against airway hyper-reactivity. Nat. Immunol. 2004, 5:1149-1156.
20. Bovenschen H.J., van de Kerkhof P.C., van Erp P.E., Woestenenk R., Joosten I., Koenen H.J. Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin. J. Invest. Dermatol. 2011, 131:1853-1860.
21. Dominguez-Villar M., Baecher-Allan C.M., Hafler D.A. Identification of T helper type 1-like, Foxp3+ regulatory T cells in human autoimmune disease. Nat. Med. 2011, 17:673-675.
22. Sanchez Rodriguez R., Pauli M.L., Neuhaus I.M., Yu S.S., Arron S.T., Harris H.W., et al. Memory regulatory T cells reside in human skin. J. Clin. Invest. 2014, 124:1027-1036.
23. Sugiyama H., Gyulai R., Toichi E., Garaczi E., Shimada S., Stevens S.R., et al. Dysfunctional blood and target tissue CD4+ CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation. J. Immunol. 2005, 174:164-173.
24. regs secrete IL-17 ex vivo and constitutively express the T(H)17 lineage-specific transcription factor RORgamma t. Proc. Natl. Acad. Sci. U.S.A. 2009, 106:8635-8640.
25. Hirahara K., Liu L., Clark R.A., Yamanaka K., Fuhlbrigge R.C., Kupper T.S. The majority of human peripheral blood CD4+CD25highFoxp3+ regulatory T cells bear functional skin-homing receptors. J. Immunol. 2006, 177:4488-4494.
26. Koenen H.J., Smeets R.L., Vink P.M., van Rijssen E., Boots A.M., Joosten I. Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood 2008, 112:2340-2352.
27. reg-mediated suppression of graft-versus-host disease after bone marrow transplantation. Biol. Blood Marrow Transplant.: J. Am. Soc. Blood Marrow Transplant. 2013, 19:1557-1565.
28. Rudensky A. Foxp3 and dominant tolerance. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2005, 360:1645-1646.
29. Himmel M.E., MacDonald K.G., Garcia R.V., Steiner T.S., Levings M.K. Helios+ and Helios- cells coexist within the natural FOXP3+ T regulatory cell subset in humans. J. Immunol. 2013, 190:2001-2008.
30. Bensinger S.J., Walsh P.T., Zhang J., Carroll M., Parsons R., Rathmell J.C., et al. Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. J. Immunol. 2004, 172:5287-5296.
31. Pandiyan P., Lenardo M.J. The control of CD4+CD25+Foxp3+ regulatory T cell survival. Biol. Direct 2008, 3:6.
32. Wu Y.Q., Borde M., Heissmeyer V., Feuerer M., Lapan A.D., Stroud J.C., et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 2006, 126:375-387.
33. Ono M., Yaguchi H., Ohkura N., Kitabayashi I., Nagamura Y., Nomura T., et al. Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature 2007, 446:685-689.
34. Pan F., Yu H., Dang E.V., Barbi J., Pan X., Grosso J.F., et al. Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells. Science 2009, 325:1142-1146.
35. Cretney E., Xin A., Shi W., Minnich M., Masson F., Miasari M., et al. The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat. Immunol. 2011, 12:304-311.
36. Li B., Greene M.I. FOXP3 actively represses transcription by recruiting the HAT/HDAC complex. Cell Cycle (Georgetown, Tex) 2007, 6:1432-1436.
37. Ochs H.D., Oukka M., Torgerson T.R. TH17 cells and regulatory T cells in primary immunodeficiency diseases. J. Allergy Clin. Immunol. 2009, 123:977-983. (quiz 84-5).
38. Bennett C.L., Christie J., Ramsdell F., Brunkow M.E., Ferguson P.J., Whitesell L., et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 2001, 27:20-21.
39. Wildin R.S., Ramsdell F., Peake J., Faravelli F., Casanova J.L., Buist N., et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 2001, 27:18-20.
40. Gavin M.A., Rasmussen J.P., Fontenot J.D., Vasta V., Manganiello V.C., Beavo J.A., et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 2007, 445:771-775.
41. reg cells: guardians for life. Nat. Immunol. 2007, 8:124-125.
42. Ohkura N., Hamaguchi M., Sakaguchi S. FOXP3+ regulatory T cells: control of FOXP3 expression by pharmacological agents. Trends Pharmacol. Sci. 2011, 32:158-166.
43. Ouyang W., Liao W., Luo C.T., Yin N., Huse M., Kim M.V., et al. Novel Foxo1-dependent transcriptional programs control T(reg) cell function. Nature 2012, 491:554-559.
44. Samstein R.M., Arvey A., Josefowicz S.Z., Peng X., Reynolds A., Sandstrom R., et al. Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell 2012, 151:153-166.
45. Baron U., Floess S., Wieczorek G., Baumann K., Grutzkau A., Dong J., et al. DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells. Eur. J. Immunol. 2007, 37:2378-2389.
46. Josefowicz S.Z., Lu L.F., Rudensky A.Y. Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 2012, 30:531-564.
47. Abbas A.K., Benoist C., Bluestone J.A., Campbell D.J., Ghosh S., Hori S., et al. Regulatory T cells: recommendations to simplify the nomenclature. Nat. Immunol. 2013, 14:307-308.
48. Shevach E.M. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 2009, 30:636-645.
49. Sakaguchi S., Miyara M., Costantino C.M., Hafler D.A. FOXP3+ regulatory T cells in the human immune system. Nat. Rev. 2010, 10:490-500.
50. Miyao T., Floess S., Setoguchi R., Luche H., Fehling H.J., Waldmann H., et al. Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 2012, 36:262-275.
51. Rubtsov Y.P., Niec R.E., Josefowicz S., Li L., Darce J., Mathis D., et al. Stability of the regulatory T cell lineage in vivo. Science 2010, 329:1667-1671.
52. Hori S. Lineage stability and phenotypic plasticity of Foxp3(+) regulatory T cells. Immunol. Rev. 2014, 259:159-172.
53. Vignali D. How many mechanisms do regulatory T cells need?. Eur. J. Immunol. 2008, 38:908-911.
54. Yamaguchi T., Wing J.B., Sakaguchi S. Two modes of immune suppression by Foxp3(+) regulatory T cells under inflammatory or non-inflammatory conditions. Semin. Immunol. 2011, 23:424-430.
55. Gondek D.C., Lu L.F., Quezada S.A., Sakaguchi S., Noelle R.J. Cutting edge: contact-mediated suppression by CD4+ CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J. Immunol. 2005, 174:1783-1786.
56. Klein L., Khazaie K., von Boehmer H. In vivo dynamics of antigen-specific regulatory T cells not predicted from behavior in vitro. Proc. Natl. Acad. Sci. U.S.A. 2003, 100:8886-8891.
57. Pandiyan P., Lenardo M. Comment on "Cutting edge: regulatory T cells do not mediate suppression via programmed cell death pathways". J. Immunol. 2012, 188:5203-5204. (author reply 4-5).
58. Pandiyan P., Zheng L., Ishihara S., Reed J., Lenardo M.J. CD4(+)CD25(+)Foxp3(+) regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4(+) T cells. Nat. Immunol. 2007, 8:1353-1362.
59. Pillai M.R., Collison L.W., Wang X., Finkelstein D., Rehg J.E., Boyd K., et al. The plasticity of regulatory T cell function. J. Immunol. 2011, 187:4987-4997.
60. Fontenot J.D., Rudensky A.Y. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat. Immunol. 2005, 6:331-337.
61. Golden J.B., McCormick T.S., Ward N.L. IL-17 in psoriasis: implications for therapy and cardiovascular co-morbidities. Cytokine 2013, 62:195-201.
62. reg cell accumulation and correlated with psoriasis disease severity. Clin. Immunol. 2010, 135:108-117.
63. Imanguli M.M., Cowen E.W., Rose J., Dhamala S., Swaim W., Lafond S., et al. Comparative analysis of FoxP3(+) regulatory T cells in the target tissues and blood in chronic graft versus host disease. Leukemia 2014, 28:2016-2027.
64. Imanguli M.M., Swaim W.D., League S.C., Gress R.E., Pavletic S.Z., Hakim F.T. Increased T-bet+ cytotoxic effectors and type I interferon-mediated processes in chronic graft-versus-host disease of the oral mucosa. Blood 2009, 113:3620-3630.
65. Rieger K., Loddenkemper C., Maul J., Fietz T., Wolff D., Terpe H., et al. Mucosal FOXP3+ regulatory T cells are numerically deficient in acute and chronic GvHD. Blood 2006, 107:1717-1723.
66. Fondi C., Nozzoli C., Benemei S., Baroni G., Saccardi R., Guidi S., et al. Increase in FOXP3+ regulatory T cells in GVHD skin biopsies is associated with lower disease severity and treatment response. Biol. Blood Marrow Transplant.: J. Am. Soc. Blood Marrow Transplant. 2009, 15:938-947.
67. Choi J., Ritchey J., Prior J.L., Holt M., Shannon W.D., Deych E., et al. In vivo administration of hypomethylating agents mitigate graft-versus-host disease without sacrificing graft-versus-leukemia. Blood 2010, 116:129-139.
68. Sanchez-Abarca L.I., Gutierrez-Cosio S., Santamaria C., Caballero-Velazquez T., Blanco B., Herrero-Sanchez C., et al. Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting. Blood 2010, 115:107-121.
69. Trzonkowski P., Dukat-Mazurek A., Bieniaszewska M., Marek-Trzonkowska N., Dobyszuk A., Juscinska J., et al. Treatment of graft-versus-host disease with naturally occurring T regulatory cells. BioDrugs: Clin. Immunotherapeut., Biopharmaceut. Gene Ther. 2013, 27:605-614.
70. reg cells undergo abortive Th1 cell differentiation due to impaired expression of IL-12 receptor beta2. Immunity 2012, 37:501-510.
71. Koch M.A., Tucker-Heard G., Perdue N.R., Killebrew J.R., Urdahl K.B., Campbell D.J. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat. Immunol. 2009, 10:595-602.
72. Cong Y., Feng T., Fujihashi K., Schoeb T.R., Elson C.O. A dominant, coordinated T regulatory cell-IgA response to the intestinal microbiota. Proc. Natl. Acad. Sci. U.S.A. 2009, 106:19256-19261.
73. Cebula A., Seweryn M., Rempala G.A., Pabla S.S., McIndoe R.A., Denning T.L., et al. Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature 2013, 497:258-262.
74. Arpaia N., Campbell C., Fan X., Dikiy S., van der Veeken J., deRoos P., et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 2013, 504:451-455.
75. Kryczek I., Wu K., Zhao E., Wei S., Vatan L., Szeliga W., et al. IL-17+ regulatory T cells in the microenvironments of chronic inflammation and cancer. J. Immunol. 2011, 186:4388-4395.
76. Li L., Boussiotis V.A. The role of IL-17-producing Foxp3+ CD4+ T cells in inflammatory bowel disease and colon cancer. Clin. Immunol. 2013, 148:246-253.
77. Ueno A., Jijon H., Chan R., Ford K., Hirota C., Kaplan G.G., et al. Increased prevalence of circulating novel IL-17 secreting Foxp3 expressing CD4+ T cells and defective suppressive function of circulating Foxp3+ regulatory cells support plasticity between Th17 and regulatory T cells in inflammatory bowel disease patients. Inflamm. Bowel Dis. 2013, 19:2522-2534.
78. Bhaskaran N., Cohen S., Zhang Y., Weinberg A., Pandiyan P. TLR-2 signaling promotes IL-17A production in CD4+CD25+Foxp3+ regulatory cells during Oropharyngeal candidiasis. Pathogens 2015, 4:90-110.
79. Pandiyan P., Conti H.R., Zheng L., Peterson A.C., Mathern D.R., Hernandez-Santos N., et al. CD4(+)CD25(+)Foxp3(+) regulatory T cells promote Th17 cells in vitro and enhance host resistance in mouse Candida albicans Th17 cell infection model. Immunity 2011, 34:422-434.
80. Feng T., Cao A.T., Weaver C.T., Elson C.O., Cong Y. Interleukin-12 converts Foxp3+ regulatory T cells to interferon-gamma-producing Foxp3+ T cells that inhibit colitis. Gastroenterology 2011, 140:2031-2043.
81. Okui T., Aoki Y., Ito H., Honda T., Yamazaki K. The presence of IL-17+/FOXP3+ double-positive cells in periodontitis. J. Dent. Res. 2012, 91:574-579.
82. Nistala K., Adams S., Cambrook H., Ursu S., Olivito B., de Jager W., et al. Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc. Natl. Acad. Sci. U.S.A. 2010, 107:14751-14756.
83. Nistala K., Moncrieffe H., Newton K.R., Varsani H., Hunter P., Wedderburn L.R. Interleukin-17-producing T cells are enriched in the joints of children with arthritis, but have a reciprocal relationship to regulatory T cell numbers. Arthritis Rheum. 2008, 58:875-887.
84. Jandus C., Bioley G., Rivals J.P., Dudler J., Speiser D., Romero P. Increased numbers of circulating polyfunctional Th17 memory cells in patients with seronegative spondylarthritides. Arthritis Rheum. 2008, 58:2307-2317.
85. Yamada H., Nakashima Y., Okazaki K., Mawatari T., Fukushi J.I., Kaibara N., et al. Th1 but not Th17 cells predominate in the joints of patients with rheumatoid arthritis. Ann. Rheum. Dis. 2008, 67:1299-1304.
86. Afzali B., Mitchell P.J., Edozie F.C., Povoleri G.A., Dowson S.E., Demandt L., et al. CD161 expression characterizes a subpopulation of human regulatory T cells that produces IL-17 in a STAT3-dependent manner. Eur. J. Immunol. 2013, 43:2043-2054.
87. Pesenacker A.M., Bending D., Ursu S., Wu Q., Nistala K., Wedderburn L.R. CD161 defines the subset of FoxP3+ T cells capable of producing proinflammatory cytokines. Blood 2013, 121:2647-2658.
88. Pesenacker A.M., Wedderburn L.R. T regulatory cells in childhood arthritis-novel insights. Expert Rev. Mol. Med. 2013, 15:e13.
89. Nylander A., Hafler D.A. Multiple sclerosis. J. Clin. Invest. 2012, 122:1180-1188.
90. Cua D.J., Sherlock J., Chen Y., Murphy C.A., Joyce B., Seymour B., et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003, 421:744-748.
91. El-Behi M., Ciric B., Dai H., Yan Y., Cullimore M., Safavi F., et al. The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat. Immunol. 2011, 12:568-575.
92. Kleinewietfeld M., Manzel A., Titze J., Kvakan H., Yosef N., Linker R.A., et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 2013, 496:518-522.
93. Lee Y.K., Menezes J.S., Umesaki Y., Mazmanian S.K. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. U.S.A. 2011, 108(Suppl. 1):4615-4622.
94. McPherson R.C., Turner D.G., Mair I., O'Connor R.A., Anderton S.M. T-bet expression by Foxp3(+) T regulatory cells is not essential for their suppressive function in CNS autoimmune disease or colitis. Front. Immunol. 2015, 6:69.
95. McClymont S.A., Putnam A.L., Lee M.R., Esensten J.H., Liu W., Hulme M.A., et al. Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. J. Immunol. 2011, 186:3918-3926.
96. Mao Y., Poschke I., Kiessling R. Tumour-induced immune suppression: role of inflammatory mediators released by myelomonocytic cells. J. Intern. Med. 2014, 276:154-170.
97. Noy R., Pollard J.W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 2014, 41:49-61.
98. Jandus C., Bioley G., Speiser D.E., Romero P. Selective accumulation of differentiated FOXP3(+) CD4 (+) T cells in metastatic tumor lesions from melanoma patients compared to peripheral blood. Cancer Immunol. Immunother. 2008, 57:1795-1805.
99. Ye J., Su X., Hsueh E.C., Zhang Y., Koenig J.M., Hoft D.F., et al. Human tumor-infiltrating Th17 cells have the capacity to differentiate into IFN-gamma+ and FOXP3+ T cells with potent suppressive function. Eur. J. Immunol. 2011, 41:936-951.
100. Noval Rivas M., Burton O.T., Wise P., Charbonnier L.M., Georgiev P., Oettgen H.C., et al. Regulatory T cell reprogramming toward a Th2-cell-like lineage impairs oral tolerance and promotes food allergy. Immunity 2015, 42:512-523.
101. reg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 2009, 31:772-786.
102. reg responses in Candida albicans immunity. PLoS Pathog. 2014, 10:e1004456.
103. Pandiyan P., Bhaskaran N., Zhang Y., Weinberg A. Isolation of T cells from mouse oral tissues. Biol. Proced. Online 2014, 16:4.
104. Bhaskaran N., Weinberg A., Pandiyan P. Th17 inflammation model of Oropharyngeal candidiasis in immunodeficient mice. J. Visual. Experim.: JoVE 2015.
105. Allan S.E., Crome S.Q., Crellin N.K., Passerini L., Steiner T.S., Bacchetta R., et al. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int. Immunol. 2007, 19:345-354.
106. McMurchy A.N., Levings M.K. In vitro generation of human T regulatory cells: generation, culture, and analysis of FOXP3-transduced T cells. Methods Mol. Biol. 2013, 946:115-132.
107. Miyara M., Yoshioka Y., Kitoh A., Shima T., Wing K., Niwa A., et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 2009, 30:899-911.
108. Cosmi L., De Palma R., Santarlasci V., Maggi L., Capone M., Frosali F., et al. Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor. J. Exp. Med. 2008, 205:1903-1916.
109. reg and Th17 cells and its role in autoimmunity. Semin. Immunol. 2013, 25:305-312.
110. Maggi L., Santarlasci V., Capone M., Peired A., Frosali F., Crome S.Q., et al. CD161 is a marker of all human IL-17-producing T-cell subsets and is induced by RORC. Eur. J. Immunol. 2010, 40:2174-2181.
111. Leveque L., Deknuydt F., Bioley G., Old L.J., Matsuzaki J., Odunsi K., et al. Interleukin 2-mediated conversion of ovarian cancer-associated CD4+ regulatory T cells into proinflammatory interleukin 17-producing helper T cells. J. Immunother. 2009, 32:101-108.
112. Yang X.O., Nurieva R., Martinez G.J., Kang H.S., Chung Y., Pappu B.P., et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 2008, 29:44-56.
113. Li L., Kim J., Boussiotis V.A. IL-1beta-mediated signals preferentially drive conversion of regulatory T cells but not conventional T cells into IL-17-producing cells. J. Immunol. 2010, 185:4148-4153.
114. Xu L., Kitani A., Fuss I., Strober W. Cutting edge: regulatory T cells induce CD4+CD25-Foxp3-T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta. J. Immunol. 2007, 178:6725-6729.
115. reg into IL-17 producers. Eur. J. Immunol. 2008, 38:3274-3281.
116. Li J., Shi J., Ren W., Wu W., Chen Z. Regulatory role of CD4(+)CD25 (+)Foxp3 (+) regulatory T cells on IL-17-secreting T cells in chronic hepatitis B patients. Dig. Dis. Sci. 2014, 59:1475-1483.
117. Pandiyan P., Yang X.P., Saravanamuthu S.S., Zheng L., Ishihara S., O'Shea J.J., et al. The role of IL-15 in activating STAT5 and fine-tuning IL-17A production in CD4 T lymphocytes. J. Immunol. 2012, 189:4237-4246.
118. Laurence A., Tato C.M., Davidson T.S., Kanno Y., Chen Z., Yao Z., et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 2007, 26:371-381.
119. Baban B., Chandler P.R., Sharma M.D., Pihkala J., Koni P.A., Munn D.H., et al. IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J. Immunol. 2009, 183:2475-2483.
120. regs to TH17-like cells in tumor-draining lymph nodes. Blood 2009, 113:6102-6111.
121. Sharma M.D., Huang L., Choi J.H., Lee E.J., Wilson J.M., Lemos H., et al. An inherently bifunctional subset of Foxp3+ T helper cells is controlled by the transcription factor eos. Immunity 2013, 38:998-1012.
122. Nyirenda M.H., Sanvito L., Darlington P.J., O'Brien K., Zhang G.X., Constantinescu C.S., et al. TLR2 stimulation drives human naive and effector regulatory T cells into a Th17-like phenotype with reduced suppressive function. J. Immunol. 2011, 187:2278-2290.
123. Ishii K.J., Koyama S., Nakagawa A., Coban C., Akira S. Host innate immune receptors and beyond: making sense of microbial infections. Cell Host Microbe 2008, 3:352-363.
124. Uematsu S., Akira S. Toll-Like receptors (TLRs) and their ligands. Handb. Exp. Pharmacol. 2008, 1-20.
125. Caramalho I., Lopes-Carvalho T., Ostler D., Zelenay S., Haury M., Demengeot J. Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide. J. Exp. Med. 2003, 197:403-411.
126. Gelman A.E., Zhang J., Choi Y., Turka L.A. Toll-like receptor ligands directly promote activated CD4+ T cell survival. J. Immunol. 2004, 172:6065-6073.
127. Komai-Koma M., Jones L., Ogg G.S., Xu D., Liew F.Y. TLR2 is expressed on activated T cells as a costimulatory receptor. Proc. Natl. Acad. Sci. U.S.A. 2004, 101:3029-3034.
128. Liu H., Komai-Koma M., Xu D., Liew F.Y. Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells. Proc. Natl. Acad. Sci. U.S.A. 2006, 103:7048-7053.
129. reg-mediated suppression of T cell activation. BMC Immunol. 2011, 12:23.
130. Oberg H.H., Juricke M., Kabelitz D., Wesch D. Regulation of T cell activation by TLR ligands. Eur. J. Cell Biol. 2011, 90:582-592.
131. Jin B., Sun T., Yu X.H., Yang Y.X., Yeo A.E. The effects of TLR activation on T-cell development and differentiation. Clin. Dev. Immunol. 2012, 2012:836485.
132. Hoffmann P., Boeld T.J., Eder R., Huehn J., Floess S., Wieczorek G., et al. Loss of FOXP3 expression in natural human CD4+CD25+ regulatory T cells upon repetitive in vitro stimulation. Eur. J. Immunol. 2009, 39:1088-1097.
133. reg suppression through direct MyD88-dependent costimulation of effector CD4+ T cells. Immunol. Lett. 2007, 108:183-188.
134. Peng G., Guo Z., Kiniwa Y., Voo K.S., Peng W., Fu T., et al. Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 2005, 309:1380-1384.
135. Sutmuller R., Garritsen A., Adema G.J. Regulatory T cells and toll-like receptors: regulating the regulators. Ann. Rheum. Dis. 2007, 66(Suppl. 3):iii91-iii95.
136. Xu D., Liu H., Komai-Koma M., Campbell C., McSharry C., Alexander J., et al. CD4+CD25+ regulatory T cells suppress differentiation and functions of Th1 and Th2 cells, Leishmania major infection, and colitis in mice. J. Immunol. 2003, 170:394-399.
137. Netea M.G., Sutmuller R., Hermann C., Van der Graaf C.A., Van der Meer J.W., van Krieken J.H., et al. Toll-like receptor 2 suppresses immunity against Candida albicans through induction of IL-10 and regulatory T cells. J. Immunol. 2004, 172:3712-3718.
138. Pasare C., Medzhitov R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 2003, 299:1033-1036.
139. Komatsu N., Mariotti-Ferrandiz M.E., Wang Y., Malissen B., Waldmann H., Hori S. Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc. Natl. Acad. Sci. U.S.A. 2009, 106:1903-1908.
140. Sutmuller R.P., den Brok M.H., Kramer M., Bennink E.J., Toonen L.W., Kullberg B.J., et al. Toll-like receptor 2 controls expansion and function of regulatory T cells. J. Clin. Invest. 2006, 116:485-494.
141. Gratz I.K., Rosenblum M.D., Abbas A.K. The life of regulatory T cells. Ann. N.Y. Acad. Sci. 2013, 1283:8-12.
142. Turka L.A., Walsh P.T. IL-2 signaling and CD4+ CD25+ Foxp3+ regulatory T cells. Front. Biosci. 2008, 13:1440-1446.
143. Chen Q., Davidson T.S., Huter E.N., Shevach E.M. Engagement of TLR2 does not reverse the suppressor function of mouse regulatory T cells, but promotes their survival. J. Immunol. 2009, 183:4458-4466.
144. Crellin N.K., Garcia R.V., Hadisfar O., Allan S.E., Steiner T.S., Levings M.K. Human CD4+ T cells express TLR5 and its ligand flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+CD25+ T regulatory cells. J. Immunol. 2005, 175:8051-8059.
145. Round J.L., Lee S.M., Li J., Tran G., Jabri B., Chatila T.A., et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 2011, 332:974-977.
146. Hall J.A., Bouladoux N., Sun C.M., Wohlfert E.A., Blank R.B., Zhu Q., et al. Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses. Immunity 2008, 29:637-649.
147. Liu J., Radler D., Illi S., Klucker E., Turan E., von Mutius E., et al. TLR2 polymorphisms influence neonatal regulatory T cells depending on maternal atopy. Allergy 2011, 66:1020-1029.
148. Takeuchi O., Akira S. MyD88 as a bottle neck in Toll/IL-1 signaling. Curr. Top. Microbiol. Immunol. 2002, 270:155-167.
149. Reynolds J.M., Pappu B.P., Peng J., Martinez G.J., Zhang Y., Chung Y., et al. Toll-like receptor 2 signaling in CD4(+) T lymphocytes promotes T helper 17 responses and regulates the pathogenesis of autoimmune disease. Immunity 2010, 32:692-702.
150. Gil M.L., Gozalbo D. Role of Toll-like receptors in systemic Candida albicans infections. Front. Biosci. 2009, 14:570-582.
151. Cho S.N., Song C.H., Jin J., Kim S.H., Rha K.S., Kim Y.M. Role of staphylococcal enterotoxin B on the differentiation of regulatory T cells in nasal polyposis. Am. J. Rhinol. Allergy 2014, 28:e17-e24.
152. O'Shea J.J., Paul W.E. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 2010, 327:1098-1102.
153. Zhu J., Paul W.E. Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors. Immunol. Rev. 2010, 238:247-262.
154. Ciofani M., Madar A., Galan C., Sellars M., Mace K., Pauli F., et al. A validated regulatory network for Th17 cell specification. Cell 2012, 151:289-303.
155. Chen Q., Yang W., Gupta S., Biswas P., Smith P., Bhagat G., et al. IRF-4-binding protein inhibits interleukin-17 and interleukin-21 production by controlling the activity of IRF-4 transcription factor. Immunity 2008, 29:899-911.
156. Reinhardt R.L., Liang H.E., Locksley R.M. Cytokine-secreting follicular T cells shape the antibody repertoire. Nat. Immunol. 2009, 10:385-393.
157. Crotty S. Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 2011, 29:621-663.
158. Qi H., Cannons J.L., Klauschen F., Schwartzberg P.L., Germain R.N. SAP-controlled T-B cell interactions underlie germinal centre formation. Nature 2008, 455:764-769.
159. Chung Y., Tanaka S., Chu F., Nurieva R.I., Martinez G.J., Rawal S., et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat. Med. 2011, 17:983-988.
160. Linterman M.A., Pierson W., Lee S.K., Kallies A., Kawamoto S., Rayner T.F., et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat. Med. 2011, 17:975-982.
161. Wollenberg I., Agua-Doce A., Hernandez A., Almeida C., Oliveira V.G., Faro J., et al. Regulation of the germinal center reaction by Foxp3+ follicular regulatory T cells. J. Immunol. 2011, 187:4553-4560.
162. Lim H.W., Hillsamer P., Banham A.H., Kim C.H. Cutting edge: direct suppression of B cells by CD4+ CD25+ regulatory T cells. J. Immunol. 2005, 175:4180-4183.
163. Lim H.W., Hillsamer P., Kim C.H. Regulatory T cells can migrate to follicles upon T cell activation and suppress GC-Th cells and GC-Th cell-driven B cell responses. J. Clin. Invest. 2004, 114:1640-1649.
164. Wing J.B., Sakaguchi S. Foxp3(+) T(reg) cells in humoral immunity. Int. Immunol. 2014, 26:61-69.
165. Li L., Patsoukis N., Petkova V., Boussiotis V.A. Runx1 and Runx3 are involved in the generation and function of highly suppressive IL-17-producing T regulatory cells. PLoS ONE 2012, 7:e45115.
166. Rudra D., deRoos P., Chaudhry A., Niec R.E., Arvey A., Samstein R.M., et al. Transcription factor Foxp3 and its protein partners form a complex regulatory network. Nat. Immunol. 2012, 13:1010-1019.
167. Chen W., Jin W., Hardegen N., Lei K.J., Li L., Marinos N., et al. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J. Exp. Med. 2003, 198:1875-1886.
168. Korn T., Bettelli E., Oukka M., Kuchroo V.K. IL-17 and Th17 cells. Annu. Rev. Immunol. 2009, 27:485-517.
169. McGeachy M.J., Cua D.J. T cells doing it for themselves: TGF-beta regulation of Th1 and Th17 cells. Immunity 2007, 26:547-549.
170. Zhou L., Lopes J.E., Chong M.M., Ivanov I.I., Min R., Victora G.D., et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 2008, 453:236-240.
171. Komatsu N., Okamoto K., Sawa S., Nakashima T., Oh-hora M., Kodama T., et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat. Med. 2014, 20:62-68.
172. Chaudhry A., Rudensky A.Y. Control of inflammation by integration of environmental cues by regulatory T cells. J. Clin. Invest. 2013, 123:939-944.
173. Chaudhry A., Rudra D., Treuting P., Samstein R.M., Liang Y., Kas A., et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 2009, 326:986-991.
174. 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. 2015, 16:197-206.
175. reg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 2009, 31:772-786.
176. Wohlfert E.A., Grainger J.R., Bouladoux N., Konkel J.E., Oldenhove G., Ribeiro C.H., et al. GATA3 controls Foxp3(+) regulatory T cell fate during inflammation in mice. J. Clin. Invest. 2011, 121:4503-4515.
177. Wang Y., Su M.A., Wan Y.Y. An essential role of the transcription factor GATA-3 for the function of regulatory T cells. Immunity 2011, 35:337-348.
178. Zhu J., Min B., Hu-Li J., Watson C.J., Grinberg A., Wang Q., et al. Conditional deletion of Gata3 shows its essential function in T(H)1-T(H)2 responses. Nat. Immunol. 2004, 5:1157-1165.
179. Wan Y.S.Y., Flavell R.A. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 2007, 445:766-770.
180. Wei G., Abraham B.J., Yagi R., Jothi R., Cui K., Sharma S., et al. Genome-wide analyses of transcription factor GATA3-mediated gene regulation in distinct T cell types. Immunity 2011, 35:299-311.
181. Zhu J., Paul W.E. Heterogeneity and plasticity of T helper cells. Cell Res. 2010, 20:4-12.
182. Hegazy A.N., Peine M., Helmstetter C., Panse I., Frohlich A., Bergthaler A., et al. Interferons direct Th2 cell reprogramming to generate a stable GATA-3(+)T-bet(+) cell subset with combined Th2 and Th1 cell functions. Immunity 2010, 32:116-128.
183. Yagi R., Junttila I.S., Wei G., Urban J.F., Zhao K., Paul W.E., et al. The transcription factor GATA3 actively represses RUNX3 protein-regulated production of interferon-gamma. Immunity 2010, 32:507-517.
184. Mosmann T.R., Coffman R.L. Heterogeneity of cytokine secretion patterns and functions of helper T cells. Adv. Immunol. 1989, 46:111-147.
185. Mosmann T.R., Coffman R.L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 1989, 7:145-173.
186. Paul W.E., Seder R.A. Lymphocyte responses and cytokines. Cell 1994, 76:241-251.
187. Seder R.A., Paul W.E. Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu. Rev. Immunol. 1994, 12:635-673.
188. Murphy T.L., Tussiwand R., Murphy K.M. Specificity through cooperation: BATF-IRF interactions control immune-regulatory networks. Nat. Rev. 2013, 13:499-509.
189. Thornton A.M., Shevach E.M. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 1998, 188:287-296.
190. Hu G., Tang Q., Sharma S., Yu F., Escobar T.M., Muljo S.A., et al. Expression and regulation of intergenic long noncoding RNAs during T cell development and differentiation. Nat. Immunol. 2013, 14:1190-1198.
191. Levine A.G., Arvey A., Jin W., Rudensky A.Y. Continuous requirement for the TCR in regulatory T cell function. Nat. Immunol. 2014, 15:1070-1078.
192. Vahl J.C., Drees C., Heger K., Heink S., Fischer J.C., Nedjic J., et al. Continuous T cell receptor signals maintain a functional regulatory T cell pool. Immunity 2014, 41:722-736.
193. Zheng Y., Chaudhry A., Kas A., deRoos P., Kim J.M., Chu T.T., et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 2009, 458:351-356.
194. Zhou X., Bailey-Bucktrout S.L., Jeker L.T., Penaranda C., Martinez-Llordella M., Ashby M., et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat. Immunol. 2009, 10:1000-1007.
195. Korn T., Anderson A.C., Bettelli E., Oukka M. The dynamics of effector T cells and Foxp3+ regulatory T cells in the promotion and regulation of autoimmune encephalomyelitis. J. Neuroimmunol. 2007, 191:51-60.
196. regs control the development of symptomatic West Nile virus infection in humans and mice. J. Clin. Invest. 2009, 119:3266-3277.
197. Chen Y., Haines C.J., Gutcher I., Hochweller K., Blumenschein W.M., McClanahan T., et al. Foxp3(+) regulatory T cells promote T helper 17 cell development in vivo through regulation of interleukin-2. Immunity 2011, 34:409-421.
198. Pandiyan P., Gartner D., Soezeri O., Radbruch A., Schulze-Osthoff K., Brunner-Weinzierl M.C. CD152 (CTLA-4) determines the unequal resistance of Th1 and Th2 cells against activation-induced cell death by a mechanism requiring PI3 kinase function. J. Exp. Med. 2004, 199:831-842.
199. Zhou Y. Regulatory T cells and viral infections. Front. Biosci. 2008, 13:1152-1170.
200. Hernandez-Santos N., Huppler A.R., Peterson A.C., Khader S.A., McKenna K.C., Gaffen S.L. Th17 cells confer long-term adaptive immunity to oral mucosal Candida albicans infections. Mucosal Immunol. 2013, 6:900-910.
201. Chaudhry A., Rudra D., Treuting P., Samstein R.M., Liang Y., Kas A., et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science (New York, NY) 2009.
202. Rosenblum M.D., Gratz I.K., Paw J.S., Lee K., Marshak-Rothstein A., Abbas A.K. Response to self antigen imprints regulatory memory in tissues. Nature 2011, 480:538-542.