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From IL-2 to IL-37: the expanding spectrum of anti-inflammatory cytokines

Nature Immunology volume 13, pages 925–931 (2012)Cite this article

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Abstract

Feedback regulatory circuits provided by regulatory T cells (Treg cells) and suppressive cytokines are an intrinsic part of the immune system, along with effector functions. Here we discuss some of the regulatory cytokines that have evolved to permit tolerance to components of self as well as the eradication of pathogens with minimal collateral damage to the host. Interleukin 2 (IL-2), IL-10 and transforming growth factor-β (TGF-β) are well characterized, whereas IL-27, IL-35 and IL-37 represent newcomers to the spectrum of anti-inflammatory cytokines. We also emphasize how information accumulated through in vitro as well as in vivo studies of genetically engineered mice can help in the understanding and treatment of human diseases.

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Figure 1: The dialog between Treg cells and DCs.
Figure 2: The dual roles of TGF-β in tolerance and immunity.
Figure 3: Members of the IL-12 family.

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References

  1. Honda, K. & Littman, D.R. The microbiome in infectious disease and inflammation. Annu. Rev. Immunol. 30, 759–795 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Lee, Y.K. & Mazmanian, S.K. Has the microbiota played a critical role in the evolution of the adaptive immune system? Science 330, 1768–1773 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Chow, J., Tang, H. & Mazmanian, S.K. Pathobionts of the gastrointestinal microbiota and inflammatory disease. Curr. Opin. Immunol. 23, 473–480 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Hill, D.A. et al. Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nat. Med. 18, 538–546 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Maloy, K.J. & Powrie, F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474, 298–306 (2011).

    CAS  PubMed  Google Scholar 

  6. Morelli, A.E. & Thomson, A.W. Tolerogenic dendritic cells and the quest for transplant tolerance. Nat. Rev. Immunol. 7, 610–621 (2007).

    CAS  PubMed  Google Scholar 

  7. Steinman, R.M., Hawiger, D. & Nussenzweig, M.C. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711 (2003).

    CAS  PubMed  Google Scholar 

  8. Tang, Q. et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat. Immunol. 7, 83–92 (2006).

    CAS  PubMed  Google Scholar 

  9. Josefowicz, S.Z., Lu, L.F. & Rudensky, A.Y. Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30, 531–564 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Sakaguchi, S., Miyara, M., Costantino, C.M. & Hafler, D.A. FOXP3+ regulatory T cells in the human immune system. Nat. Rev. Immunol. 10, 490–500 (2010).

    CAS  PubMed  Google Scholar 

  11. Bilate, A.M. & Lafaille, J.J. Induced CD4+Foxp3+ regulatory T cells in immune tolerance. Annu. Rev. Immunol. 30, 733–758 (2012).

    CAS  PubMed  Google Scholar 

  12. Allan, S.E. et al. CD4+ T-regulatory cells: toward therapy for human diseases. Immunol. Rev. 223, 391–421 (2008).

    CAS  PubMed  Google Scholar 

  13. Pot, C., Apetoh, L. & Kuchroo, V.K. Type 1 regulatory T cells (Tr1) in autoimmunity. Semin. Immunol. 23, 202–208 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Roncarolo, M.G. et al. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol. Rev. 212, 28–50 (2006).

    CAS  PubMed  Google Scholar 

  15. Cheng, M.H. & Anderson, M.S. Monogenic autoimmunity. Annu. Rev. Immunol. 30, 393–427 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Bennett, C.L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20–21 (2001).

    CAS  PubMed  Google Scholar 

  17. Wildin, R.S. et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 27, 18–20 (2001).

    CAS  PubMed  Google Scholar 

  18. Ito, T. et al. Two functional subsets of FOXP3+ regulatory T cells in human thymus and periphery. Immunity 28, 870–880 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Zheng, Y. et al. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 445, 936–940 (2007).

    CAS  PubMed  Google Scholar 

  20. Campbell, D.J. & Koch, M.A. Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat. Rev. Immunol. 11, 119–130 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Duhen, T., Duhen, R., Lanzavecchia, A., Sallusto, F. & Campbell, D.J. Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells. Blood 119, 4430–4440 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Miyara, M. et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30, 899–911 (2009).

    CAS  PubMed  Google Scholar 

  23. Vignali, D.A., Collison, L.W. & Workman, C.J. How regulatory T cells work. Nat. Rev. Immunol. 8, 523–532 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Shevach, E.M. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 30, 636–645 (2009).

    CAS  PubMed  Google Scholar 

  25. 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. 23, 424–430 (2011).

    CAS  PubMed  Google Scholar 

  26. Qureshi, O.S. et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332, 600–603 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Miyara, M. et al. Human FoxP3+ regulatory T cells in systemic autoimmune diseases. Autoimmun. Rev. 10, 744–755 (2011).

    CAS  PubMed  Google Scholar 

  28. Hippen, K.L., Riley, J.L., June, C.H. & Blazar, B.R. Clinical perspectives for regulatory T cells in transplantation tolerance. Semin. Immunol. 23, 462–468 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Miyara, M., Wing, K. & Sakaguchi, S. Therapeutic approaches to allergy and autoimmunity based on FoxP3+ regulatory T-cell activation and expansion. J. Allergy Clin. Immunol. 123, 749–755 (2009).

    CAS  PubMed  Google Scholar 

  30. Steinman, L., Merrill, J.T., McInnes, I.B. & Peakman, M. Optimization of current and future therapy for autoimmune diseases. Nat. Med. 18, 59–65 (2012).

    CAS  PubMed  Google Scholar 

  31. Malek, T.R. & Castro, I. Interleukin-2 receptor signaling: at the interface between tolerance and immunity. Immunity 33, 153–165 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Schorle, H., Holtschke, T., Hunig, T., Schimpl, A. & Horak, I. Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature 352, 621–624 (1991).

    CAS  PubMed  Google Scholar 

  33. Kündig, T.M. et al. Immune responses in interleukin-2-deficient mice. Science 262, 1059–1061 (1993).

    PubMed  Google Scholar 

  34. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Pillars article: immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 186, 3808–3821 (2011).

    CAS  PubMed  Google Scholar 

  35. Caudy, A.A., Reddy, S.T., Chatila, T., Atkinson, J.P. & Verbsky, J.W. CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes. J. Allergy Clin. Immunol. 119, 482–487 (2007).

    CAS  PubMed  Google Scholar 

  36. Pociot, F. et al. Genetics of type 1 diabetes: what's next? Diabetes 59, 1561–1571 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Hulme, M.A., Wasserfall, C.H., Atkinson, M.A. & Brusko, T.M. Central role for interleukin-2 in type 1 diabetes. Diabetes 61, 14–22 (2012).

    CAS  PubMed  Google Scholar 

  38. Tang, Q. et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 28, 687–697 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Yamanouchi, J. et al. Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nat. Genet. 39, 329–337 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Setoguchi, R., Hori, S., Takahashi, T. & Sakaguchi, S. Homeostatic maintenance of natural Foxp3+CD25+CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J. Exp. Med. 201, 723–735 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Rabinovitch, A., Suarez-Pinzon, W.L., Shapiro, A.M., Rajotte, R.V. & Power, R. Combination therapy with sirolimus and interleukin-2 prevents spontaneous and recurrent autoimmune diabetes in NOD mice. Diabetes 51, 638–645 (2002).

    CAS  PubMed  Google Scholar 

  42. Grinberg-Bleyer, Y. et al. IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells. J. Exp. Med. 207, 1871–1878 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Liston, A., Siggs, O.M. & Goodnow, C.C. Tracing the action of IL-2 in tolerance to islet-specific antigen. Immunol. Cell Biol. 85, 338–342 (2007).

    CAS  PubMed  Google Scholar 

  44. Laurence, A. et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26, 371–381 (2007).

    CAS  PubMed  Google Scholar 

  45. Yang, X.P. et al. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat. Immunol. 12, 247–254 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Quintana, F.J. et al. Aiolos promotes TH17 differentiation by directly silencing Il2 expression. Nat. Immunol. 13, 770–777 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Chen, Y. et al. Foxp3+ regulatory T cells promote T helper 17 cell development in vivo through regulation of interleukin-2. Immunity 34, 409–421 (2011).

    CAS  PubMed  Google Scholar 

  48. Pandiyan, P. 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 34, 422–434 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Crotty, S. Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 29, 621–663 (2011).

    CAS  PubMed  Google Scholar 

  50. Deenick, E.K., Ma, C.S., Brink, R. & Tangye, S.G. Regulation of T follicular helper cell formation and function by antigen presenting cells. Curr. Opin. Immunol. 23, 111–118 (2011).

    CAS  PubMed  Google Scholar 

  51. Vinuesa, C.G. & Cyster, J.G. How T cells earn the follicular rite of passage. Immunity 35, 671–680 (2011).

    CAS  PubMed  Google Scholar 

  52. Morita, R. et al. Human blood CXCR5+CD4+ T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 34, 108–121 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Ballesteros-Tato, A. et al. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 36, 847–856 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Johnston, R.J., Choi, Y.S., Diamond, J.A., Yang, J.A. & Crotty, S. STAT5 is a potent negative regulator of TFH cell differentiation. J. Exp. Med. 209, 243–250 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Malek, T.R. & Khan, W.N. IL-2: Fine-tuning the Germinal Center Reaction. Immunity 36, 702–704 (2012).

    CAS  PubMed  Google Scholar 

  56. Ahmadzadeh, M. & Rosenberg, S.A. IL-2 administration increases CD4+CD25hiFoxp3+ regulatory T cells in cancer patients. Blood 107, 2409–2414 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Koreth, J. et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N. Engl. J. Med. 365, 2055–2066 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Saadoun, D. et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N. Engl. J. Med. 365, 2067–2077 (2011).

    CAS  PubMed  Google Scholar 

  59. Moore, K.W., de Waal Malefyt, R., Coffman, R.L. & O'Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001).

    CAS  PubMed  Google Scholar 

  60. O'Garra, A., Barrat, F.J., Castro, A.G., Vicari, A. & Hawrylowicz, C. Strategies for use of IL-10 or its antagonists in human disease. Immunol. Rev. 223, 114–131 (2008).

    CAS  PubMed  Google Scholar 

  61. Sabat, R. et al. Biology of interleukin-10. Cytokine Growth Factor Rev. 21, 331–344 (2010).

    CAS  PubMed  Google Scholar 

  62. Commins, S., Steinke, J.W. & Borish, L. The extended IL-10 superfamily: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29. J. Allergy Clin. Immunol. 121, 1108–1111 (2008).

    CAS  PubMed  Google Scholar 

  63. Li, M.O. & Flavell, R.A. Contextual regulation of inflammation: a duet by transforming growth factor-β and interleukin-10. Immunity 28, 468–476 (2008).

    PubMed  Google Scholar 

  64. Saraiva, M. & O'Garra, A. The regulation of IL-10 production by immune cells. Nat. Rev. Immunol. 10, 170–181 (2010).

    CAS  PubMed  Google Scholar 

  65. Murray, P.J. & Smale, S.T. Restraint of inflammatory signaling by interdependent strata of negative regulatory pathways. Nat. Immunol. 13, 916–924 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Izcue, A., Coombes, J.L. & Powrie, F. Regulatory lymphocytes and intestinal inflammation. Annu. Rev. Immunol. 27, 313–338 (2009).

    CAS  PubMed  Google Scholar 

  67. Kühn, R., Lohler, J., Rennick, D., Rajewsky, K. & Muller, W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274 (1993).

    PubMed  Google Scholar 

  68. Glocker, E.O., Kotlarz, D., Klein, C., Shah, N. & Grimbacher, B. IL-10 and IL-10 receptor defects in humans. Ann. NY Acad. Sci. 1246, 102–107 (2011).

    CAS  PubMed  Google Scholar 

  69. Glocker, E.O. et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361, 2033–2045 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Gregori, S. et al. Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway. Blood 116, 935–944 (2011).

    Google Scholar 

  71. Barrat, F.J. et al. In vitro generation of interleukin 10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J. Exp. Med. 195, 603–616 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Huber, S. et al. Th17 cells express interleukin-10 receptor and are controlled by Foxp3− and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity 34, 554–565 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Chaudhry, A. et al. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity 34, 566–578 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Murai, M. et al. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat. Immunol. 10, 1178–1184 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Rubtsov, Y.P. et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28, 546–558 (2008).

    CAS  PubMed  Google Scholar 

  76. Rousset, F. et al. Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc. Natl. Acad. Sci. USA 89, 1890–1893 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Defrance, T. et al. Interleukin 10 and transforming growth factor β cooperate to induce anti-CD40-activated naive human B cells to secrete immunoglobulin A. J. Exp. Med. 175, 671–682 (1992).

    CAS  PubMed  Google Scholar 

  78. Li, D. et al. Targeting self- and foreign antigens to dendritic cells via DC-ASGPR generates IL-10-producing suppressive CD4+ T cells. J. Exp. Med. 209, 109–121 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Li, M.O. & Flavell, R.A. TGF-β: a master of all T cell trades. Cell 134, 392–404 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Tran, D.Q. TGF-β: the sword, the wand, and the shield of FOXP3+ regulatory T cells. J. Mol. Cell Biol. 4, 29–37 (2012).

    CAS  PubMed  Google Scholar 

  81. Konkel, J.E. & Chen, W. Balancing acts: the role of TGF-β in the mucosal immune system. Trends Mol. Med. 17, 668–676 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Regateiro, F.S., Howie, D., Cobbold, S.P. & Waldmann, H. TGF-β in transplantation tolerance. Curr. Opin. Immunol. 23, 660–669 (2011).

    CAS  PubMed  Google Scholar 

  83. Shull, M.M. et al. Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Li, X. et al. IL-35 is a novel responsive anti-inflammatory cytokine–a new system of categorizing anti-inflammatory cytokines. PLoS ONE 7, e33628 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Chen, W. et al. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Dardalhon, V. et al. IL-4 inhibits TGF-β-induced Foxp3+ T cells and, together with TGF-β, generates IL-9+IL-10+Foxp3− effector T cells. Nat. Immunol. 9, 1347–1355 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Sun, C.M. et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204, 1775–1785 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Coombes, J.L. et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J. Exp. Med. 204, 1757–1764 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Liu, Y. et al. A critical function for TGF-β signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat. Immunol. 9, 632–640 (2008).

    CAS  PubMed  Google Scholar 

  90. Ghoreschi, K. et al. Generation of pathogenic TH17 cells in the absence of TGF-beta signalling. Nature 467, 967–971 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Gutcher, I. et al. Autocrine transforming growth factor-β1 promotes in vivo Th17 cell differentiation. Immunity 34, 396–408 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Li, M.O., Wan, Y.Y. & Flavell, R.A. T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity 26, 579–591 (2007).

    CAS  PubMed  Google Scholar 

  93. Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V.K. IL-17 and Th17 cells. Annu. Rev. Immunol. 27, 485–517 (2009).

    CAS  PubMed  Google Scholar 

  94. Cerutti, A. & Rescigno, M. The biology of intestinal immunoglobulin A responses. Immunity 28, 740–750 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Litinskiy, M.B. et al. DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat. Immunol. 3, 822–829 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Dullaers, M. et al. A T cell-dependent mechanism for the induction of human mucosal homing immunoglobulin A-secreting plasmablasts. Immunity 30, 120–129 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Shi, M. et al. Latent TGF-β structure and activation. Nature 474, 343–349 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Tran, D.Q. et al. GARP (LRRC32) is essential for the surface expression of latent TGF-β on platelets and activated FOXP3+ regulatory T cells. Proc. Natl. Acad. Sci. USA 106, 13445–13450 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Travis, M.A. et al. Loss of integrin αVβ8 on dendritic cells causes autoimmunity and colitis in mice. Nature 449, 361–365 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Grainger, J.R. et al. Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-β pathway. J. Exp. Med. 207, 2331–2341 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).

    CAS  PubMed  Google Scholar 

  102. Li, M.O., Sanjabi, S. & Flavell, R.A. Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 25, 455–471 (2006).

    CAS  PubMed  Google Scholar 

  103. Marie, J.C., Liggitt, D. & Rudensky, A.Y. Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor. Immunity 25, 441–454 (2006).

    CAS  PubMed  Google Scholar 

  104. Vignali, D.A. & Kuchroo, V.K. IL-12 family cytokines: immunological playmakers. Nat. Immunol. 13, 722–728 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Molle, C., Goldman, M. & Goriely, S. Critical role of the IFN-stimulated gene factor 3 complex in TLR-mediated IL-27p28 gene expression revealing a two-step activation process. J. Immunol. 184, 1784–1792 (2010).

    CAS  PubMed  Google Scholar 

  106. Pflanz, S. et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells. Immunity 16, 779–790 (2002).

    CAS  PubMed  Google Scholar 

  107. Villarino, A. et al. The IL-27R (WSX-1) is required to suppress T cell hyperactivity during infection. Immunity 19, 645–655 (2003).

    CAS  PubMed  Google Scholar 

  108. Hamano, S. et al. WSX-1 is required for resistance to Trypanosoma cruzi infection by regulation of proinflammatory cytokine production. Immunity 19, 657–667 (2003).

    CAS  PubMed  Google Scholar 

  109. Pot, C., Apetoh, L. & Kuchroo, V.K. Type 1 regulatory T cells (Tr1) in autoimmunity. Semin. Immunol. 23, 202–208 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Wojno, E.D. & Hunter, C.A. New directions in the basic and translational biology of interleukin-27. Trends Immunol. 33, 91–97 (2012).

    CAS  PubMed  Google Scholar 

  111. Apetoh, L. et al. The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat. Immunol. 11, 854–861 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Ansari, N.A. et al. IL-27 and IL-21 are associated with T cell IL-10 responses in human visceral leishmaniasis. J. Immunol. 186, 3977–3985 (2011).

    CAS  PubMed  Google Scholar 

  113. Wojno, E.D. et al. A role for IL-27 in limiting T regulatory cell populations. J. Immunol. 187, 266–273 (2011).

    CAS  PubMed  Google Scholar 

  114. Cox, J.H. et al. IL-27 promotes T cell-dependent colitis through multiple mechanisms. J. Exp. Med. 208, 115–123 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Stumhofer, J.S. et al. A role for IL-27p28 as an antagonist of gp130-mediated signaling. Nat. Immunol. 11, 1119–1126 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Dibra, D. et al. Interleukin-30: a novel antiinflammatory cytokine candidate for prevention and treatment of inflammatory cytokine-induced liver injury. Hepatology 55, 1204–1214 (2012).

    CAS  PubMed  Google Scholar 

  117. Collison, L.W. et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450, 566–569 (2007).

    CAS  PubMed  Google Scholar 

  118. Chaturvedi, V., Collison, L.W., Guy, C.S., Workman, C.J. & Vignali, D.A. Cutting edge: Human regulatory T cells require IL-35 to mediate suppression and infectious tolerance. J. Immunol. 186, 6661–6666 (2011).

    CAS  PubMed  Google Scholar 

  119. Collison, L.W. et al. IL-35-mediated induction of a potent regulatory T cell population. Nat. Immunol. 11, 1093–1101 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Bettini, M., Castellaw, A.H., Lennon, G.P., Burton, A.R. & Vignali, D.A. Prevention of autoimmune diabetes by ectopic pancreatic beta-cell expression of interleukin-35. Diabetes 61, 1519–1526 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Kochetkova, I., Golden, S., Holderness, K., Callis, G. & Pascual, D.W. IL-35 stimulation of CD39+ regulatory T cells confers protection against collagen II-induced arthritis via the production of IL-10. J. Immunol. 184, 7144–7153 (2010).

    CAS  PubMed  Google Scholar 

  122. Seyerl, M. et al. Human rhinoviruses induce IL-35-producing Treg via induction of B7–H1 (CD274) and sialoadhesin (CD169) on DC. Eur. J. Immunol. 40, 321–329 (2010).

    CAS  PubMed  Google Scholar 

  123. Dunn, E., Sims, J.E., Nicklin, M.J. & O'Neill, L.A. Annotating genes with potential roles in the immune system: six new members of the IL-1 family. Trends Immunol. 22, 533–536 (2001).

    CAS  PubMed  Google Scholar 

  124. Kumar, S. et al. Interleukin-1F7B (IL-1H4/IL-1F7) is processed by caspase-1 and mature IL-1F7B binds to the IL-18 receptor but does not induce IFN-γ production. Cytokine 18, 61–71 (2002).

    CAS  PubMed  Google Scholar 

  125. Nold, M.F. et al. IL-37 is a fundamental inhibitor of innate immunity. Nat. Immunol. 11, 1014–1022 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. McNamee, E.N. et al. Interleukin 37 expression protects mice from colitis. Proc. Natl. Acad. Sci. USA 108, 16711–16716 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Bulau, A.M. et al. In vivo expression of interleukin-37 reduces local and systemic inflammation in concanavalin A-induced hepatitis. ScientificWorldJournal 11, 2480–2490 (2011).

    PubMed  PubMed Central  Google Scholar 

  128. Sakaguchi, S., Powrie, F. & Ransohoff, R.M. Re-establishing immunological self-tolerance in autoimmune disease. Nat. Med. 18, 54–58 (2012).

    CAS  PubMed  Google Scholar 

  129. Schwager, K. et al. The antibody-mediated targeted delivery of interleukin-10 inhibits endometriosis in a syngeneic mouse model. Hum. Reprod. 26, 2344–2352 (2011).

    CAS  PubMed  Google Scholar 

  130. Hawiger, D. et al. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J. Exp. Med. 194, 769–779 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Tarbell, K.V. et al. Dendritic cell-expanded, islet-specific CD4+CD25+CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice. J. Exp. Med. 204, 191–201 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Mukhopadhaya, A. et al. Selective delivery of beta cell antigen to dendritic cells in vivo leads to deletion and tolerance of autoreactive CD8+ T cells in NOD mice. Proc. Natl. Acad. Sci. USA 105, 6374–6379 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank A. Howes for reading and proofing the manuscript. Supported by the Medical Research Council, UK (U117565642 to A.O.G.) and the US National Institutes of Health (ARO50770-02 and AIO82715 to V.P.).

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Authors and Affiliations

  1. Baylor Institute for Immunology Research, Dallas, Texas, USA

    Jacques Banchereau & Virginia Pascual

  2. Division of Immunoregulation, MRC National Institute for Medical Research, Mill Hill, London, UK

    Anne O'Garra

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  1. Jacques Banchereau
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  2. Virginia Pascual
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Correspondence to Jacques Banchereau.

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Banchereau, J., Pascual, V. & O'Garra, A. From IL-2 to IL-37: the expanding spectrum of anti-inflammatory cytokines. Nat Immunol 13, 925–931 (2012). https://doi.org/10.1038/ni.2406

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