Do natural T regulatory cells become activated to antigen specific T regulatory cells in transplantation and in autoimmunity?

Frontiers in Immunology

Volumn 4, Issue AUG, 2013, Pages

  Hall, Bruce M ^a   Tran, Giang T ^a   Verma, Nirupama D ^a   Plain, Karren M ^a   Robinson, Catherine M ^a   Nomura, Masaru ^a   Hodgkinson, Suzanne J ^a  

^a UNIVERSITY OF NEW SOUTH WALES   (Australia)

Author keywords

Antigen specific Treg; Immune tolerance; nTreg; Th1 like Treg; Th2 like Treg

Indexed keywords

ANTIGEN; GAMMA INTERFERON; GAMMA INTERFERON RECEPTOR; INTERLEUKIN 2; INTERLEUKIN 27; INTERLEUKIN 4; INTERLEUKIN 5; INTERLEUKIN 6; T LYMPHOCYTE RECEPTOR; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR FOXP3; TRANSFORMING GROWTH FACTOR BETA;

ANTIGEN SPECIFICITY; AUTOIMMUNITY; CD4+ CD25+ T LYMPHOCYTE; CELL TRANSPLANTATION; CELLULAR IMMUNITY; GENE EXPRESSION; HUMAN; HUMAN CELL; IMMUNE RESPONSE; IMMUNOLOGICAL TOLERANCE; REGULATORY T LYMPHOCYTE; REVIEW; T LYMPHOCYTE ACTIVATION; TH1 CELL; TH2 CELL;

EID: 84883723718     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2013.00208     Document Type: Review

References (230)

1. Gershon RK, Kondo K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology (1970) 18:723-37.
2. Gershon RK, Kondo K. Infectious immunological tolerance. Immunology (1971) 21:903-14.
3. Gershon RK, Cohen P, Hencin R, Liebhaber SA. Suppressor T cells. J Immunol (1972) 108:586-90.
4. Basten A, Fazekas de St Groth B. Special regulatory T-cell review: T-cell dependent suppression revisited. Immunology (2008) 123:33-9. doi:10.1111/j.1365-2567.2007.02772.x
5. Moller G. Do suppressor T cells exist? Scand J Immunol (1988) 27:247-50. doi:10.1111/j.1365-3083.1988.tb02344.x
6. Hall BM, Jelbart ME, Dorsch SE. Suppressor T cells in rats with prolonged cardiac allograft survival after treatment with cyclosporine. Transplantation (1984) 37:595-600. doi:10.1097/00007890-198406000-00014
7. Hall BM. Mechanisms maintaining enhancement of allografts. I. Demonstration of a specific suppressor cell. J Exp Med (1985) 161:123-33. doi:10.1084/jem.161.1.123
8. Hall BM, Jelbart ME, Gurley KE, Dorsch SE. Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. Mediation of specific suppression by T helper/inducer cells. J Exp Med (1985) 162:1683-94. doi:10.1084/jem.162.5.1683
9. Qin S, Cobbold SP, Pope H, Elliott J, Kioussis D, Davies J, et al. "Infectious" transplantation tolerance. Science (1993) 259:974-7. doi:10.1126/science.8094901
10. + T cells. J Immunol (1989) 143:499-506.
11. + suppressor cell and its mechanisms of action. J Exp Med (1990) 171:141-57. doi:10.1084/jem.171.1.141
12. + suppressor cell on the presence of alloantigen and cytokines, including interleukin-2. Transplantation (1993) 55:374-80. doi:10.1097/00007890-199302000-00027
13. Dallman MJ, Shiho O, Page TH, Wood KJ, Morris PJ. Peripheral tolerance to alloantigen results from altered regulation of the interleukin 2 pathway. J Exp Med (1991) 173:79-87. doi:10.1084/jem.173.1.79
14. Hall BM, Dorsch SE. Cells mediating allograft rejection. Immunol Rev (1984) 77:31-59. doi:10.1111/j.1600-065X.1984.tb00717.x
15. Cheng IKP, Dorsch SE, Hall BM. The regulation of autoantibody production in Heymann's nephritis by T lymphocyte subsets. Lab Invest (1988) 59:780-8.
16. Hall BM, Dorsch S, Roser B. The cellular basis of allograft rejection in vivo. II. The nature of memory cells mediating second set heart graft rejection. J Exp Med (1978) 148:890-902. doi:10.1084/jem.148.4.890
17. Hall BM, Dorsch S, Roser B. The cellular basis of allograft rejection in vivo. I. The cellular requirements for first-set rejection of heart grafts. J Exp Med (1978) 148:878-89. doi:10.1084/jem.148.4.890
18. 3+ regulatory cells. Nat Rev Immunol (2011) 11:119-30. doi:10.1038/nri2916
19. 25). J Immunol (1995) 155:1151-64.
20. + regulatory T cells: thymus or periphery. J Clin Invest (2003) 112:1310-2. doi:10.1172/JCI200320274
21. 3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol (2007) 19:345-54. doi:10.1093/intimm/dxm014
22. 3. Mol Ther (2008) 16:194-202. doi:10.1038/sj.mt.6300341
23. 25+ T cells: evidence for two distinct regulatory mechanisms. Eur J Immunol (2001) 31:1637-45. doi:10.1002/1521-4141(200106)31:6<1637::AID-IMMU1637>3.0.CO;2-T
24. Malek TR, 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 (2002) 17:167-78. doi:10.1016/S1074-7613(02)00367-9
25. 3 expression. Nature (2007) 445:766-70. doi:10.1038/nature05479
26. Seddiki N, Santner-Nanan B, Martinson J, Zaunders J, Sasson S, Landay A, et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med (2006) 203:1693-700. doi:10.1084/jem.20060468
27. Aerts NE, Dombrecht EJ, Ebo DG, Bridts CH, Stevens WJ, De Clerck LS. Activated T cells complicate the identification of regulatory T cells in rheumatoid arthritis. Cell Immunol (2008) 251:109-15. doi:10.1016/j.cellimm.2008.04.008
28. Lim HW, Kim CH. Loss of IL-7 receptor alpha on T cells defines terminally differentiated B cell-helping effector cells. J Immunol (2007) 179:7448-56.
29. Vella A, Teague TK, Ihle J, Kappler J, Marrack P. Interleukin 4 (IL-4) or IL-7 prevents the death of resting T cells: stat6 is probably not required for the effect of IL-4. J Exp Med (1997) 186:325-30. doi:10.1084/jem.186.2.325
30. 3+ regulatory T cells. J Immunol (2007) 178:280-90.
31. 3+ T regulatory cells. J Immunol (2006) 177:5115-21.
32. 3+ regulatory T cell development. J Immunol (2008) 181:3285-90.
33. + T cell receptors. Immunity (2004) 21:267-77. doi:10.1016/j.immuni.2004.07.009
34. Hsieh CS, Zheng Y, Liang Y, Fontenot JD, Rudensky AY. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat Immunol (2006) 7:401-10. doi:10.1038/ni1318
35. Weiner H, da Cunha AP, Quintana F, Wu H. Oral tolerance. Immunol Rev (2011) 241:241-59. doi:10.1111/j.1600-065X.2011.01017.x
36. + T-cell inhibits antigen-specific T-cell responses and prevents colitis. Nature (1997) 389:737-42. doi:10.1038/39614
37. Groux H. Type 1 T-regulatory cells: their role in the control of immune responses. Transplantation (2003) 75:8S-12. doi:10.1097/01.TP.0000067944.90241.BD
38. 3+ conventional T cells. Eur J Immunol (2007) 37:2378-89. doi:10.1002/eji.200737594
39. 3 expression is required for the induction of therapeutic tissue tolerance. J Immunol (2012) 189:3947-56. doi:10.4049/jimmunol.1200449
40. Belkaid Y. Regulatory T cells and infection: a dangerous necessity. Nat Rev Immunol (2007) 7:875-87. doi:10.1038/nri2189
41. Francis RS, Feng G, Tha-in T, Lyons IS, Wood KJ, Bushell A. Induction of transplantation tolerance converts potential effector T cells into graft-protective regulatory T cells. Eur J Immunol (2011) 41:726-38. doi:10.1002/eji.201040509
42. Wood KJ, Bushell A, Jones ND. Immunological unresponsiveness to alloantigen in vivo: a role for regulatory T cells. Immunol Rev (2011) 241:119-32. doi:10.1111/j.1600-065X.2011.01013.x
43. Wood KJ, Bushell A, Hester J. Regulatory immune cells in transplantation. Nat Rev Immunol (2012) 12:417-30. doi:10.1038/nri3227
44. Yadav M, Louvet C, Davini D, Gardner JM, Martinez-Llordella M, Bailey-Bucktrout S, et al. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med (2012) 209:1713-22. doi:10.1084/jem.20120822
45. 3+ regulatory T cells. Int J Clin Exp Pathol (2013) 6:116-23.
46. 25+ T cells alloactivated ex vivo by IL-2 or IL-4, become potent alloantigen specific inhibitors of rejection with different phenotypes, suggesting Th1 and Th2 responses activate by separate pathways. Blood (2009) 113:479-87. doi:10.1182/blood-2008-05-156612
47. Sakai K, Zamvil SS, Mitchell DJ, Hodgkinson S, Rothbard JB, Steinman L. Prevention of experimental encephalomyelitis with peptides that block interaction of T cells with major histocompatibility complex proteins. Proc Natl Acad Sci U S A (1989) 86:9470-4. doi:10.1073/pnas.86.23.9470
48. Smilek D, Wraith D, Hodgkinson SJ, Dwivedy S, Steinman L, McDevitt H. A single amino-acid change in a myelin-basic protein peptide confers the capacity to prevent rather than induce experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A (1991) 88:9633-7. doi:10.1073/pnas.88.21.9633
49. 25+4+ regulatory T cells in anti-myelin basic protein T cell receptor transgenic mice. Proc Natl Acad Sci U S A (2002) 99:8213-8. doi:10.1073/pnas.122224799
50. Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J, et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med (2004) 199:1455-65. doi:10.1084/jem.20040139
51. 25+CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice. J Exp Med (2007) 204:191-201. doi:10.1084/jem.20061631
52. Tonkin DR, He J, Barbour G, Haskins K. Regulatory T cells prevent transfer of type 1 diabetes in NOD mice only when their antigen is present in vivo. J Immunol (2008) 181:4516-22.
53. Huter EN, Stummvoll GH, Dipaolo RJ, Glass DD, Shevach EM. Cutting edge: antigen-specific TGF beta-induced regulatory T cells suppress Th17-mediated autoimmune disease. J Immunol (2008) 181:8209-13.
54. Yu P, Gregg RK, Bell JJ, Ellis JS, Divekar R, Lee HH, et al. Specific T regulatory cells display broad suppressive functions against experimental allergic encephalomyelitis upon activation with cognate antigen. J Immunol (2005) 174:6772-80.
55. 25+ T cells, but not IL-4 or TGF-β and cannot induce tolerance to linked antigens. Transplantation (2007) 83:1075-84. doi:10.1097/01.tp.0000259553.66185.2f
56. 25+ T regulatory cells that suppress autoimmunity. Blood (2012) 119:4441-50. doi:10.1182/blood-2011-12-396101
57. 25- T cells determines rejection or tolerance. Transpl Immunol (2006) 15:311-8. doi:10.1016/j.trim.2006.01.003
58. 25+ immunoregulatory T cells is antigen nonspecific. J Immunol (2000) 164:183-90.
59. 25- T cells in mixed lymphocyte cultures. Transpl Immunol (2008) 18:291-300. doi:10.1016/j.trim.2007.09.002
60. Lee SY, Cho ML, Oh HJ, Ryu JG, Park MJ, Jhun JY, et al. Interleukin-2/anti-interleukin-2 monoclonal antibody immune complex suppresses collagen-induced arthritis in mice by fortifying interleukin-2/STAT5 signalling pathways. Immunology (2012) 137:305-16. doi:10.1111/imm.12008
61. 3+ regulatory T cell therapy in transplantation. J Mol Cell Biol (2012) 4:11-21. doi:10.1093/jmcb/mjr047
62. Hall BM. Transplantation tolerance: a 1988 perspective. Transplant Proc (1989) 21:816-9.
63. Baecher-Allan C, Wolf E, Hafler DA. MHC class II expression identifies functionally distinct human regulatory T cells. J Immunol (2006) 176:4622-31.
64. +CD8- thymocytes that express L-selectin protect rats from diabetes upon adoptive transfer. Eur J Immunol (1996) 26:2702-8. doi:10.1002/eji.1830261123
65. + regulatory T cells. J Exp Med (2004) 199:303-13. doi:10.1084/jem.20031562
66. 25+ and CD8+CD28- T suppressor cells. Hum Immunol (2004) 65:1297-306. doi:10.1016/j.humimm.2004.09.004
67. +25+ T-regulatory cells are potent inhibitors of GVHD and BM graft rejection. Blood (2004) 104:3804-12. doi:10.1182/blood-2004-05-1850
68. 25+ regulatory T cells protects from lethal acute GVHD. Blood (2005) 105:2220-6. doi:10.1182/blood-2004-05-2044
69. 25+ Tregs. Clin Immunol (2008) 126:291-302. doi:10.1016/j.clim.2007.11.008
70. Siegmund K, Feuerer M, Siewert C, Ghani S, Haubold U, Dankof A, et al. Migration matters: regulatory T-cell compartmentalization determines suppressive activity in vivo. Blood (2005) 106:3097-104. doi:10.1182/blood-2005-05-1864
71. 3+ regulatory T cells results in tissue-specific inflammatory disease. J Exp Med (2007) 204:1335-47. doi:10.1084/jem.20070081
72. Koch MA, Tucker-Heard G, Perdue NR, Killebrew JR, Urdahl KB, Campbell DJ. The transcription factor T-bet controls regulatory T cell homeostasis and function during type-1 inflammation. Nat Immunol (2009) 10:595-602. doi:10.1038/ni.1731
73. Zheng Y, Chaudhry A, Kas A, Deroos P, Kim JM, Chu T-T, et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses. Nature (2009) 458:351-6. doi:10.1038/nature07674
74. 3+ Treg in the presence of lineage-specific polarizing factors. Proc Natl Acad Sci U S A (2010) 107:19402-7. doi:10.1073/pnas.1008247107
75. 3+ follicular regulatory T cells control the germinal center response. Nat Med (2011) 17:975-82. doi:10.1038/nm.2425
76. Mullen AC, High FA, Hutchins AS, Lee HW, Villarino AV, Livingston DM, et al. Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science (2001) 282:1907-10. doi:10.1126/science.1059835
77. Wang Y, Su MA, Wan YY. An essential role of the transcription factor GATA-3 for the function of regulatory T cells. Immunity (2011) 35:337-48. doi:10.1016/j.immuni.2011.08.012
78. 3+ regulatory T cells in humans. Proc Natl Acad Sci U S A (2009) 106:4793-8. doi:10.1073/pnas.0900408106
79. + T cells. Science (2010) 327:1098-102. doi:10.1126/science.1178334
80. Hidalgo LG, Halloran PF. Role of IFN-gamma in allograft rejection. Crit Rev Immunol (2002) 22:317-49. doi:10.1615/CritRevImmunol.v22.i4.50
81. Wood KJ, Feng G, Wei B, Sawitzki B, Bushell AR. Interferon gamma: friend or foe? Transplantation (2007) 84:S4-5. doi:10.1097/01.tp.0000269115.60728.b1
82. Caretto D, Katzman SD, Villarino AV, Gallo E, Abbas AK. Cutting edge: the Th1 response inhibits the generation of peripheral regulatory T cells. J Immunol (2010) 184:30-4. doi:10.4049/jimmunol.0903412
83. 25+ T cells represent major subsets of human peripheral blood memory T cells migrating in response to CCL1/I-309. Eur J Immunol (2002) 32:3506-14. doi:10.1002/1521-4141(200212)32:12<3506::AID-IMMU3506>3.0.CO;2-#
84. Sis B, Famulski KS, Allanach KL, Zhu L-F, Halloran PF. IFN-γ prevents early perforin-granzyme-mediated destruction of kidney allografts by inducing donor class I products in the kidney. Am J Transplant (2007) 7:2301-10. doi:10.1111/j.1600-6143.2007.01947.x
85. Mitchell RN, Lichtman AH. The link between IFN-γ and allograft arteriopathy: is the answer NO? J Clin Invest (2004) 114:762-4. doi:10.1172/JCI200422927
86. Tellides G, Pober JS. Interferon-g axis in graft atherosclerosis. Circ Res (2007) 100:622-32. doi:10.1161/01.RES.0000258861.72279.29
87. Hart-Matyas M, Nejat S, Jordan JL, Hirsch GM, Lee TDJ. IFN-γ and Fas/FasL pathways cooperate to induce medial cell loss and neointimal lesion formation in allograft vasculopathy. Transplant Immunol (2010) 22:157-64. doi:10.1016/j.trim.2009.10.004
88. Hall BM, Bishop GA, Duggin GG, Horvath JS, Philips J, Tiller DJ. Increased expression of HLA-DR antigens on renal tubular cells in renal transplants: relevance to the rejection response. Lancet (1984) 2:247-51. doi:10.1016/S0140-6736(84)90297-6
89. Halloran PF, Afrouzian M, Ramassar V, Urmson J, Zhu LF, Helms LM, et al. Interferon-gamma acts directly on rejecting renal allografts to prevent graft necrosis. Am J Pathol (2001) 158:215-26. doi:10.1016/S0002-9440(10)63960-0
90. Halloran PF, Miller LW, Urmson J, Ramassar V, Zhu LF, Kneteman NM, et al. IFN-gamma alters the pathology of graft rejection: protection from early necrosis. J Immunol (2001) 166:7072-81.
91. Coley SM, Ford ML, Hanna SC, Wagener ME, Kirk AD, Larsen CP. IFN-γ dictates allograft fate via opposing effects on the graft and on recipient CD8 T cell responses. J Immunol (2008) 182:225-33.
92. Feuerer M, Eulenburg K, Loddenkemper C, Hamann A, Huehn J. Self-limitation of Th1-mediated inflammation by IFN-gamma. J Immunol (2006) 176:2857-63.
93. Willenborg DO, Fordham S, Bernard CC, Cowden WB, Ramshaw IA. IFN-gamma plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. J Immunol (1996) 157:3223-7.
94. Willenborg DO, Fordham SA, Staykova MA, Ramshaw IA, Cowden WB. Interferon-gamma is critical to the control of murine autoimmune encephalomyelitis and regulates both in the periphery and in the target tissue: a possible role for nitric oxide. J Immunol (1999) 163:5278-86.
95. O'Brien NC, Charlton B, Cowden WB, Willenborg DO. Nitric oxide plays a critical role in the recovery of lewis rats from experimental autoimmune encephalomyelitis and the maintenance of resistance to reinduction. J Immunol (1999) 163:6841-7.
96. O'Brien NC, Charlton B, Cowden WB, Willenborg DO. Inhibition of nitric oxide synthase initiates relapsing remitting experimental autoimmune encephalomyelitis in rats, yet nitric oxide appears to be essential for clinical expression of disease. J Immunol (2001) 167:5904-12.
97. Staykova MA, Paridaen JT, Cowden WB, Willenborg DO. Nitric oxide contributes to resistance of the Brown Norway rat to experimental autoimmune encephalomyelitis. Am J Pathol (2005) 166:147-57. doi:10.1016/S0002-9440(10)62240-7
98. Verma ND, Boyd R, Robinson C, Plain KM, Tran GT, Hall BM. Interleukin-12p70 prolongs allograft survival by induction of interferon gamma and nitric oxide production. Transplantation (2006) 82:1324-33. doi:10.1097/01.tp.0000239519.56358.c1
99. Brok HPM, Heidt PJ, van der Meide PH, Zurcher C, Vossen JM. Interferon-gamma prevents graft-versus-host disease after allogeneic bone marrow transplantation in mice. J Immunol (1993) 151:6451-9.
100. Guillonneau C, Hill M, Hubert FX, Chiffoleau E, Hervé C, Li XL, et al. CD40Ig treatment results in allograft acceptance mediated by CD8CD45RC T cells, IFN-gamma, and indoleamine 2,3-dioxygenase. J Clin Invest (2007) 117:1096-106. doi:10.1172/JCI28801
101. Sawitzki B, Kingsley CI, Oliveira V, Karim M, Herber M, Wood KJ. IFN-gamma production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo. J Exp Med (2005) 201:1925-35. doi:10.1084/jem.20050419
102. 25+ regulatory T cells in antitumor immune response. J Immunol (2005) 175:4433-40.
103. 3+ regulatory T cells that prevent allograft rejection: potential avenues for cellular therapy. Transplantation (2008) 86:578-89. doi:10.1097/TP.0b013e3181806a60
104. 3+ regulatory T cells. Eur J Immunol (2008) 38:2512-27. doi:10.1002/eji.200838411
105. Feng G, Chan T, Wood KJ, Bushell A. Donor reactive regulatory T cells. Curr Opin Organ Transplant (2009) 14:69-80. doi:10.1097/MOT.0b013e32832c58f1
106. Feng A, Nadig SN, Bäckdahl L, Beck S, Francis RS, Schiopu A, et al. Functional regulatory T cells produced by inhibiting cyclic nucleotide phosphodiesterase type 3 prevent allograft rejection. Sci Transl Med (2011) 3:83ra40. doi:10.1126/scitranslmed.3002099
107. Feng G, Wood KJ, Bushell A. Regulatory T cell enrichment by IFN-γ conditioning. Methods Mol Biol (2011) 677:281-301. doi:10.1007/978-1-60761-869-0_20
108. + Tregs. J Clin Invest (2006) 116:2434-41.
109. 3 and protect against airway hyper-reactivity. Nat Immunol (2004) 5:1149-56. doi:10.1038/ni1122
110. Redjimi N, Raffin C, Raimbaud I, Pignon P, Matsuzaki J, Odunis K, et al. CXCR3+ T regulatory cells selectively accumulate in human ovarian carcinomas to limit type I immunity. Cancer Res (2012) 72:4351-60. doi:10.1158/0008-5472.CAN-12-0579
111. 3+IFN-gamma+ T cells exhibit selective suppressive capacity. Eur J Immunol (2009) 39:2703-15. doi:10.1002/eji.200839097
112. McClymont SA, Putnam AL, Lee MR, Esensten JH, Liu W, Hulme MA, et al. Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. J Immunol (2011) 186:3918-26. doi:10.4049/jimmunol.1003099
113. 3+ regulatory T cells in human autoimmune disease. Nat Med (2011) 17:673-5. doi:10.1038/nm.2389
114. 3+IFN-γ+ human induced T regulatory cells are induced by interferon-? and suppress alloresponses nonspecifically. Hum Immunol (2011) 72:699-707. doi:10.1016/j.humimm.2011.05.020
115. 25+ regulatory T cells in the absence of STAT1: increased susceptibility to autoimmune disease. J Exp Med (2004) 199:25-34. doi:10.1084/jem.20020509
116. Hall AO, Beiting DP, Tato C, John B, Oldenhove G, Lombana CG, et al. The cytokines interleukin 27 and interferon-? promote distinct Treg cell populations required to limit infection-induced pathology. Immunity (2012) 37(23):511-23. doi:10.1016/j.immuni.2012.06.014
117. Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol (2003) 3:133-46. doi:10.1038/nri1001
118. Manetti R, Parronchi P, Giudizi MG, Piccinni MP, Maggi E, Trinchieri G, et al. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med (1993) 177:1199-204. doi:10.1084/jem.177.4.1199
119. Valenzuela J, Schmidt C, Mescher M. The roles of IL-12 in providing a third signal for clonal expansion of naive CD8 T cells. J Immunol (2002) 169(12):6842-9.
120. Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, Chan S, et al. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med (1989) 170:827-45. doi:10.1084/jem.170.3.827
121. Manetti R, Gerosa F, Giudizi MG, Biagiotti R, Parronchi P, Piccinni MP, et al. Interleukin 12 induces stable priming for interferon gamma (IFN-gamma) production during differentiation of human T helper (Th) cells and transient IFN-gamma production in established Th2 cell clones. J Exp Med (1994) 179:1273-83. doi:10.1084/jem.179.4.1273
122. Gately MK, Renezetti LM, Magram J, Stern AS, Adorini L, Gubler U, et al. The interleukin-12-receptor system: role in normal and pathological responses. Annu Rev Immunol (1998) 16:495-521. doi:10.1146/annurev.immunol.16.1.495
123. + T cells through IL-12 produced by Listeria-induced macrophages. Science (1993) 260:547-9. doi:10.1126/science.8097338
124. Kaplan MH, Sun YL, Hoey T, Grusby MJ. Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature (1996) 382:174-7. doi:10.1038/382174a0
125. Williamson E, Garside P, Bradley JA, Mowat AM. IL-12 is a central mediator of acute-graft versus-host disease in mice. J Immunol (1996) 157:689-99.
126. Sykes M, Szot GL, Nguyen PL, Pearson DA. Interleukin-12 inhibits murine graft-versus-host disease. Blood (1995) 86:2429-38.
127. Yang YG, Dey BR, Sergio JJ, Pearson DA, Sykes M. Donor-derived interferon gamma is required for inhibition of acute graft-versus-host disease by interleukin 12. J Clin Invest (1998) 102:2126-35. doi:10.1172/JCI4992
128. Dey BR, Yang YG, Szot GL, Pearson DA, Sykes M. Interleukin-12 inhibits graft-versus-host disease through an Fas-mediated mechanism associated with alterations in donor T-cell activation and expansion. Blood (1998) 91:3315-22.
129. Tarrant TK, Silver PB, Wahlstern JL, Rizzo LV, Chan CC, Wiggert B, et al. Interleukin 12 protects from a T helper 1-mediated autoimmune disease, experimental autoimmune uveitis, through a mechanism involving interferon gamma, nitric oxide and apoptosis. J Exp Med (1999) 189:219. doi:10.1084/jem.189.2.219
130. Zhang GX, Yu S, Gran B, Li J, Iglienti I, Chen X, et al. Role of IL-12 receptor beta 1 in regulation of T cell response by APC in experimental autoimmune encephalomyelitis. J Immunol (2003) 171:4485-92.
131. Xu H, Rizzo LV, Silver PB, Caspi RR. Uveitogenicity is associated with a Th1-like lymphokine profile: cytokine-dependent modulation of early and committed effector T cells in experimental autoimmune uveitis. Cell Immunol (1997) 178:69-78. doi:10.1006/cimm.1997.1121
132. Yokoi H, Kato K, Kezuka T, Sakai J, Usui M, Yagita H, et al. Prevention of experimental autoimmune uveoretinitis by monoclonal antibody to interleukin-12. Eur J Immunol (1997) 27:641-6. doi:10.1002/eji.1830270310
133. Adorini L. Interleukin-12, a key cytokine in Th1-mediated autoimmune diseases. Cell Mol Life Sci (1999) 55:1610-25. doi:10.1007/s000180050400
134. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature (2003) 421:744-8. doi:10.1038/nature01355
135. Zhang GX, Gran B, Yu S, Li J, Siglienti I, Chen X, et al. 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 (2003) 170:2153-60.
136. Krakowski M, Owens T. Interferon-gamma confers resistance to experimental allergic encephalomyelitis. Eur J Immunol (1996) 26:1641-6. doi:10.1002/eji.1830260735
137. 25+ regulatory T cells. J Immunol (2008) 181:3870-6.
138. 3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity (2009) 31:772-86. doi:10.1016/j.immuni.2009.10.001
139. Hall AO, Silver JS, Hunter CA. The immunobiology of IL-27. Adv Immunol (2012) 115:1-44. doi:10.1016/B978-0-12-394299-9.00001-1
140. Villarino A, Larkin JR, Saris CJ, Caton AJ, Lucas S, Wong T, et al. Positive and negative regulation of the IL-27 receptor during lymphoid activation. J Immunol (2005) 174(12):7684-91.
141. Villarino A, Hibbert L, Lieberman L, Wilson E, Mak T, Yoshida H, et al. The IL-27R (WSX-1) is required to suppress T cell hyperactivity during infection. Immunity (2003) 19:645-55. doi:10.1016/S1074-7613(03)00300-5
142. Stumhofer JS, Silver JS, Laurence A, Porrett PM, Harris TH, Turka LA, et al. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat Immunol (2007) 8(12):1363-71. doi:10.1038/ni1537
143. Yoshida H, Miyazaki Y. Regulation of immune responses by interleukin-27. Immunol Rev (2008) 226:234-47. doi:10.1111/j.1600-065X.2008.00710.x
144. 3 gene by the Th1 cytokines: the role of IL-27-induced STAT1. J Immunol (2009) 182:1041-9.
145. Das MP, Nicholson LB, Greer JM, Kuchroo VK. Autopathogenic T helper cell type 1 (Th1) and protective Th2 clones differ in their recognition of the autoantigenic peptide of myelin proteolipid protein. J Exp Med (1997) 186:867-76. doi:10.1084/jem.186.6.867
146. Falcone M, Bloom BR. A T helper cell 2 (Th2) immune response against non-self antigens modifies the cytokine profile of autoimmune T cells and protects against experimental allergic encephalomyelitis. J Exp Med (1997) 185:901-7. doi:10.1084/jem.185.5.901
147. + T-cell subsets in autoimmunity. Curr Opin Immunol (1997) 9:872-83. doi:10.1016/S0952-7915(97)80192-6
148. Spicer ST, Ha H, Boyd RA, He XY, Carter N, Tran G, et al. IL-4 therapy prevents the development of proteinuria in active Heymann nephritis by inhibition of Tc1 cells. J Immunol (2001) 167:3725-33.
149. Racke MK, Bonomo A, Scott DE, Canella B, Levine A, Raine CS, et al. Cytokine-induced immune deviation as therapy for inflammatory autoimmune disease. J Exp Med (1994) 180:1961-6. doi:10.1084/jem.180.5.1961
150. Tran GT, Carter N, He XY, Spicer TS, Plain KM, Nicolls M, et al. Reversal of experimental allergic encephalomyelitis with non-mitogenic, non-depleting anti-CD3 mAb therapy with a preferential effect on Th1 cells that is augmented by IL-4. Int Immunol (2001) 13:1109-20. doi:10.1093/intimm/13.9.1109
151. Rott O, Fleischer B, Cash E. Interleukin-10 prevents experimental allergic encephalomyelitis in rats. Eur J Immunol (1994) 24:1434-40. doi:10.1002/eji.1830240629
152. Zaccone P, Phillips J, Conget I, Gomis R, Haskins K, Minty A, et al. Interleukin-13 prevents autoimmune diabetes in NOD mice. Diabetes (1999) 48:1522-8. doi:10.2337/diabetes.48.8.1522
153. + T cells in vivo. Differential expression of IL-2 and IL-4 mRNA in recipients of cardiac allografts. J Immunol (1992) 148:1308-14.
154. Kupiec-Weglinski JW, Wasowska B, Papp I, Schmidbauer G, Sayegh MH, Baldwin WMD, et al. CD4 mAb therapy modulates alloantibody production and intracardiac graft deposition in association with selective inhibition of Th1 lymphokines. J Immunol (1993) 151:5053-61.
155. Mottram PL, Han WR, Purcell LJ, McKenzie IFC, Hancock WW. Increased expression of IL-4 and IL-10 and decreased expression of IL-2 and interferon-gamma in long-surviving mouse heart allografts after brief CD4-monoclonal antibody therapy. Transplantation (1995) 59:559-65. doi:10.1097/00007890-199559040-00021
156. Sayegh MH, Akalin E, Hancock WW, Russell ME, Carpenter CB, Linsley PS, et al. CD28-B7 blockade after alloantigenic challenge in vivo inhibits Th1 cytokines but spares Th2. J Exp Med (1995) 181:1869-74. doi:10.1084/jem.181.5.1869
157. Takeuchi T, Ueki T, Sunaga S, Ikuta K, Sasaki Y, Li B, et al. Murine interleukin 4 transgenic heart allograft survival prolonged with down-regulation of TH1 cytokine mRNA in grafts. Transplantation (1997) 64:152-7. doi:10.1097/00007890-199707150-00026
158. Plain KM, Chen J, Merten S, He XY, Davidson C, Hall BM. Induction of specific tolerance to allografts in rats by therapy with non-mitogenic, non depleting anti-CD3 monoclonal antibody: association with Th2 cytokines not anergy. Transplantation (1999) 67:605-13. doi:10.1097/00007890-199902270-00020
159. Chen N, Field EH. Enhanced type 2 and diminished type 1 cytokines in neonatal tolerance. Transplantation (1995) 59:933-41. doi:10.1097/00007890-199504150-00002
160. Chen N, Gao Q, Field EH. Expansion of memory TH2 cells over TH1 cells in neonatal primed mice. Transplantation (1995) 60:1187-93. doi:10.1097/00007890-199512000-00002
161. Chen N, Gao Q, Field EH. Prevention of TH1 responses is critical for tolerance. Transplantation (1996) 61:1076-83. doi:10.1097/00007890-199604150-00016
162. Field EH, Rouse TM. Alloantigen priming after total lymphoid irradiation alters alloimmune cytokine responses. Transplantation (1995) 60:695-701. doi:10.1097/00007890-199510150-00014
163. Field EH, Rouse TM, Gao Q, Chang B. Associations between enhanced Th1/Th2 cytokine profile and donor T cell chimerism following total lymphoid irradiation. Hum Immunol (1997) 52:144-50. doi:10.1016/S0198-8859(96)00291-1
164. Plain KM, Boyd R, Verma N, Robinson C, Tran G, Hodgkinson SJ, et al. Transplant tolerance associated with a Th1 response and not broken by IL-4. IL-5 and TGF-beta blockade or Th1 cytokine administration. Transplantation (2007) 83:764-73. doi:10.1097/01.tp.0000256326.11647.2e
165. Waaga-Gasser AM, Grimm MR, Lutz J, Lange V, Lenhard SM, Aviles B, et al. Regulatory allospecific T cell clones abrogate chronic allograft rejection. J Am Soc Nephrol (2009) 20:820-30. doi:10.1681/ASN.2008020164
166. + suppressor T cells that are not dependent upon IL-4. J Immunol (1998) 161:5147-56.
167. Takeda K, Tanaka T, Shi W, Matsumoto M, Minami M, Kashiwamura S, et al. Essential role of Stat6 in IL-4 signalling. Nature (1996) 380:627-30. doi:10.1038/380627a0
168. Kaplan MH, Schindler U, Smiley ST, Grusby MJ. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity (1996) 4:313-9. doi:10.1016/S1074-7613(00)80439-2
169. Pillemer BB, Qi Z, Melgert B, Oriss TB, Ray P, Ray A. STAT6 activation confers upon T helper cells resistance to suppression by regulatory T cells. J Immunol (2009) 183:155-63. doi:10.4049/jimmunol.0803733
170. Campbell DJ. Regulatory T cells GATA have it. Immunity (2011) 35:313-5. doi:10.1016/j.immuni.2011.09.002
171. 3+ regulatory T cell fate during inflammation in mice. J Clin Invest (2011) 121:4503-15. doi:10.1172/JCI57456
172. 3 expression and the formation of regulatory T cells. PLoS Biol (2007) 5:e329. doi:10.1371/journal.pbio.0050329
173. Gorelik L, Constant S, Flavell RA. Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J Exp Med (2002) 195:1499-505. doi:10.1084/jem.20012076
174. Gorelik L, Fields PE, Flavell RA. Cutting edge: TGF-beta inhibits Th type 2 development through inhibition of GATA-3 expression. J Immunol (2000) 165:4773-7.
175. 3- effector T cells. Nat Immunol (2008) 9:1347-55. doi:10.1038/ni.1677
176. Veldhoen M, Uyttenhove C, van Snick J, Helmby H, Westendorf A, Buer J, et al. Transforming growth factor-beta "reprograms" the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol (2008) 9:1341-6. doi:10.1038/ni.1659
177. + regulatory T cell function. J Autoimmun (2005) 25:112-20. doi:10.1016/j.jaut.2005.04.001
178. 25+ T cell suppressor function. Eur J Immunol (2004) 34:366-76. doi:10.1002/eji.200324455
179. 25+ T regulatory cell-mediated suppression. J Immunol (2005) 174:7645-53.
180. He XY, Verma N, Chen J, Robinson C, Boyd R, Hall BM. IL-5 prolongs allograft survival by downregulating IL-2 and IFN-gamma cytokines. Transplant Proc (2001) 33:703-4. doi:10.1016/S0041-1345(00)02212-0
181. Brustle A, Heink S, Huber M, Rosenplanter C, Stadelmann C, Yu P, et al. The development of inflammatory Th-17 cells requires interferon-regulatory factor 4. Nat Immunol (2007) 8:958-66. doi:10.1038/ni1500
182. Akbari O, Freeman GJ, Meyer EH, Greenfield EA, Chang TT, Sharpe AH, et al. Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat Med (2002) 8:1024-32. doi:10.1038/nm745
183. 3+ regulatory T-cell expansion, maintenance and IL-10 production during helminth infection. Eur J Immunol (2013) 43:705-15. doi:10.1002/eji.201242794
184. Taylor JJ, Mohrs M, Pearce EJ. Regulatory T cell responses develop in parallel to Th responses and control the magnitude and phenotype of the Th effector population. J Immunol (2006) 176:5839-47.
185. + cells contribute to Th2 polarization during helminth infection by suppressing Th1 response development. J Immunol (2004) 173:1224-31.
186. Whary MT, Fox JG. Th1-mediated pathology in mouse models of human disease is ameliorated by concurrent Th2 responses to parasite antigens. Curr Top Med Chem (2004) 4:531-8. doi:10.2174/1568026043451276
187. 3+ regulatory T cells that interfere with immune response and parasite clearance in BALB/c mice. J Immunol (2011) 186:4295-305. doi:10.4049/jimmunol.1001920
188. 25+ regulatory T cells control Leishmania major persistence and immunity. Nature (2002) 420:502-7. doi:10.1038/nature01152
189. 25+ regulatory T cells inhibit protective immunity to filarial parasites in vivo. J Immunol (2007) 179:4626-34.
190. 3+ regulatory T cells in mice infected with the filarial parasite Brugia malayi. J Immunol (2008) 181:6456-66.
191. Babu S, Blauvelt V, Kumaraswami V, Nutman TB. Regulatory networks induced by live parasites impair both Th1 and Th2 pathways in patent lymphatic filariasis: implications for parasitic persistence. J Immunol (2006) 176:3248-56.
192. Maizels RM, Balic A, Gomez-Escobar N, Nair M, Taylor MD, Allen JE. Helminth parasites - masters of regulation. Immunol Rev (2004) 201:89-116. doi:10.1111/j.0105-2896.2004.00191.x
193. 25+ T cells, which regulate Th2-mediated granuloma formation in mice. J Immunol (2005) 174:1962-70.
194. Rausch S, Huehn J, Kirchhoff D, Rzepecka J, Schnoeller C, Pillai S, et al. Functional analysis of effector and regulatory T cells in a parasitic nematode infection. Infect Immun (2008) 76:1908-19. doi:10.1128/IAI.01233-07
195. Tadokoro CE, Vallochi AL, Rios LS, Martins GA, Schlesinger D, Mosca T, et al. Experimental autoimmune encephalomyelitis can be prevented and cured by infection with Trypanosoma cruzi. J Autoimmun (2004) 23:103-15. doi:10.1016/j.jaut.2004.05.003
196. Gruden-Movsesijan A, Ilic N, Mostarica-Stojkovic M, Stosic-Grujicic S, Milic M, Sofronic-Milosavljevic L. Mechanisms of modulation of experimental autoimmune encephalomyelitis by chronic Trichinella spiralis infection in Dark Agouti rats. Parasite Immunol (2010) 32:450-9. doi:10.1111/j.1365-3024.2010.01207.x
197. Walsh KP, Brady MT, Finlay CM, Boon L, Mills KH. Infection with a helminth parasite attenuates autoimmunity through TGF-beta-mediated suppression of Th17 and Th1 responses. J Immunol (2009) 183:1577-86. doi:10.4049/jimmunol.0803803
198. Ledingham DL, McAlister V, Ehigiator HN, Giacomantonio C, Theal M, Lee TD. Prolongation of allograft survival by nematodes. Transplantation (1996) 61:184-9. doi:10.1097/00007890-199601270-00003
199. Liwski R, Zhou J, McAlister V, Lee TD. Prolongation of allograft survival by Nippostrongylus brasiliensis is associated with decreased allospecific cytotoxic T lymphocyte activity and development of T cytotoxic cell type 2 cells. Transplantation (2000) 69:1912-22. doi:10.1097/00007890-200005150-00029
200. Zeng Z, Ming C, Zhen Z, Sun R, Chen W. Can an allograft become harmonious with its recipient by analogous mechanisms to the long-term survival of a parasite in its host? Transplantation is similar to parasitism and chronic parasite infection can prolong allograft survival. Med Hypotheses (2005) 65:1047-50. doi:10.1016/j.mehy.2005.06.027
201. Maizels RM, Yazdanbakhsh M. T-cell regulation in helminth parasite infections: implications for inflammatory diseases. Chem Immunol Allergy (2008) 94:112-23. doi:10.1159/000154944
202. Correale J, Farez M. Association between parasite infection and immune responses in multiple sclerosis. Ann Neurol (2007) 61:97-108. doi:10.1002/ana.21067
203. Correale J, Farez MF. The impact of parasite infections on the course of multiple sclerosis. J Neuroimmunol (2011) 233:6-11. doi:10.1016/j.jneuroim.2011.01.002
204. Summers RW, Elliott DE, Urban JFJ, Thompson RA, Weinstock JV. Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial. Gastroenterology (2005) 128:825-32. doi:10.1053/j.gastro.2005.01.005
205. Elliott DE, Weinstock JV. Helminthic therapy: using worms to treat immune-mediated disease. Adv Exp Med Biol (2009) 666:157-66. doi:10.1007/978-1-4419-1601-3_12
206. Jackson JA, Friberg IM, Little S, Bradley JE. Review series on helminths, immune modulation and the hygiene hypothesis: immunity against helminths and immunological phenomena in modern human populations: coevolutionary legacies? Immunology (2009) 126:18-27. doi:10.1111/j.1365-2567.2008.03010.x
207. Beriou G, Costantino CM, Ashley CW, Yang L, Kuchroo VK, Baecher-Allan C, et al. IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood (2009) 113:4240-9. doi:10.1182/blood-2008-10-183251
208. + regulatory lymphocyte generation: implications in graft-versus-host disease and antitumor immunity. J Immunol (2007) 179:7593-604.
209. + regulatory T cells control TH17 responses in a Stat3-dependent manner. Science (2009) 326:986-91. doi:10.1126/science.1172702
210. Huber M, Steinwald V, Guralnik A, Brustle A, Kleemann P, Rosenplanter C, et al. IL-27 inhibits the development of regulatory T cells via STAT3. Int Immunol (2008) 20:223-34. doi:10.1093/intimm/dxm139
211. Chaudhry A, Samstein RM, Treuting P, Liang Y, Pils MC, Heinrich JM, et al. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity (2011) 34:566-78. doi:10.1016/j.immuni.2011.03.018
212. + T cells in an interleukin-10-dependent manner. Immunity (2011) 34:554-65. doi:10.1016/j.immuni.2011.01.020
213. 3+ Tregs secrete IL-17 ex vivo and constitutively express the Th17 lineage-specific transcription factor RORgamma t. Proc Natl Acad Sci U S A (2009) 106:8635-40. doi:10.1073/pnas.0900621106
214. Crome SQ, Clive B, Wang AY, Kang CY, Chow V, Yu J, et al. Inflammatory effects of ex vivo human Th17 cells are suppressed by regulatory T cells. J Immunol (2010) 185:3199-208. doi:10.4049/jimmunol.1000557
215. 3+ naive regulatory T cells. J Immunol (2011) 187:5196-202. doi:10.4049/jimmunol.1101742
216. + regulatory T cells into proinflammatory interleukin 17-producing helper T cells. J Immunother (2009) 32:101-8. doi:10.1097/CJI.0b013e318195b59e
217. Battaglia A, Buzzonetti A, Baranello C, Fanelli M, Fossati M, Catzola V, et al. IL-21 synergises with IL-2 to enhance TCR-induced human T cell proliferation and counteracts IL-2/TGF-β-induced regulatory T cell development. Immunology (2012) 139:109-20. doi:10.1111/imm.12061
218. Lim HW, Hillsamer P, Kim CH. 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) 114:1640-9. doi:10.1172/JCI22325
219. 25+ regulatory T cells. J Immunol (2005) 175:4180-3.
220. Sawant DV, Sehra S, Nguyen ET, Jadhav R, Englert K, Shinnakasu R, et al. Bcl6 controls the Th2 inflammatory activity of regulatory T cells by repressing Gata3 function. J Immunol (2012) 189:4759-69. doi:10.4049/jimmunol.1201794
221. Tang Q, Lee K. Regulatory T-cell therapy for transplantation: how many cells do we need? Curr Opin Organ Transplant (2012) 17:349-54. doi:10.1097/MOT.0b013e328355a992
222. + T cell subsets; differences between naïve and antigen specific T regulatory cells. Curr Opin Immunol (2011) 23:1-7. doi:10.1016/j.coi.2011.07.012
223. 3. Science (2003) 299:1057-61. doi:10.1126/science.1079490
224. + regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med (2000) 192:303-10. doi:10.1084/jem.192.2.303
225. Mantel PY, Schmidt-Weber CB. Transforming growth factor-beta: recent advances on its role in immune tolerance. Methods Mol Biol (2011) 677:303-38. doi:10.1007/978-1-60761-869-0_21
226. Collison LW, Pillai MR, Chaturvedi V, Vignali DA. Regulatory T cell suppression is potentiated by target T cells in a cell contact, IL-35- and IL-10-dependent manner. J Immunol (2009) 182:6121-8. doi:10.4049/jimmunol.0803646
227. 3+ regulatory T cells confer infectious tolerance in a TGF-β-dependent manner. J Exp Med (2008) 205:1975-81. doi:10.1084/jem.20080308
228. Del Prete G, De Carli M, Almerigogna F, Giudizi MG, Biagiotti R, Romagnani P. Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cells and inhibits their antigen specific proliferation and cytokine production. J Immunol (1993) 150:353-60.
229. Assenmacher M, Schmitz J, Radbruch A. Flow cytometric determination of cytokines in activated murine T helper lymphocytes: expression of interleukin-10 in interferon-gamma and interleukin-4-expression cells. Eur J Immunol (1994) 24:1097-101. doi:10.1002/eji.1830240513
230. 3- Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis. J Exp Med (2007) 204:285-97. doi:10.1084/jem.20061886