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IL-12 family cytokines: immunological playmakers

Nature Immunology volume 13, pages 722728 (2012) | Download Citation

Abstract

The interleukin 12 (IL-12) family is unique in having the only heterodimeric cytokines, including IL-12, IL-23, IL-27 and IL-35. This feature endows these cytokines with a unique set of connections and functional interactions not shared by other cytokine families. Despite sharing many structural features and molecular partners, cytokines of the IL-12 family mediate surprisingly diverse functional effects. Here we discuss the unique and unusual structural and functional characteristics of this cytokine family. We outline how cells might interpret seemingly similar cytokine signals to give rise to the diverse functional outcomes that characterize this cytokine family. We also discuss the therapeutic implications of this complexity.

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References

  1. 1.

    & Interleukin-35: odd one out or part of the family? Immunol. Rev. 226, 248–262 (2008).

  2. 2.

    & Molecular interactions within the IL-6/IL-12 cytokine/receptor superfamily. Immunol. Res. 51, 5–14 (2011).

  3. 3.

    New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nat. Rev. Immunol. 5, 521–531 (2005).

  4. 4.

    , & Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu. Rev. Immunol. 25, 221–242 (2007).

  5. 5.

    Langrish, C.L. et al. IL-12 and IL-23: master regulators of innate and adaptive immunity. Immunol. Rev. 202, 96–105 (2004).

  6. 6.

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

  7. 7.

    & New directions in the basic and translational biology of interleukin-27. Trends Immunol. 33, 91–97 (2012).

  8. 8.

    & Advances in understanding the anti-inflammatory properties of IL-27. Immunol. Lett. 117, 123–130 (2008).

  9. 9.

    , , & Induction of regulatory Tr1 cells and inhibition of TH17 cells by IL-27. Semin. Immunol. 23, 438–445 (2011).

  10. 10.

    , & How regulatory T cells work. Nat. Rev. Immunol. 8, 523–532 (2008).

  11. 11.

    IL-12/IL-13 axis in allergic asthma. J. Allergy Clin. Immunol. 107, 9–18 (2001).

  12. 12.

    & The IL-17/IL-23 axis of inflammation in cancer: friend or foe? Curr. Opin. Investig. Drugs 10, 543–549 (2009).

  13. 13.

    & IL-23 and Th17 cytokines in intestinal homeostasis. Mucosal Immunol. 1, 339–349 (2008).

  14. 14.

    IL-23/IL-17 biology and therapeutic considerations. J. Immunotoxicol. 5, 43–46 (2008).

  15. 15.

    & The link between IL-23 and Th17 cell-mediated immune pathologies. Semin. Immunol. 19, 372–376 (2007).

  16. 16.

    , & IL-23: changing the verdict on IL-12 function in inflammation and autoimmunity. Expert Opin. Ther. Targets 9, 1123–1136 (2005).

  17. 17.

    et al. The IL-27 p28 subunit binds cytokine-like factor 1 to form a cytokine regulating NK and T cell activities requiring IL-6R for signaling. J. Immunol. 183, 7692–7702 (2009).

  18. 18.

    Cytokine-like factor 1 (CLF1): life after development? Cytokine 55, 325–329 (2011).

  19. 19.

    & The structure of interleukin-23 reveals the molecular basis of p40 subunit sharing with interleukin-12. J. Mol. Biol. 382, 931–941 (2008).

  20. 20.

    et al. Crystal structures of the pro-inflammatory cytokine interleukin-23 and its complex with a high-affinity neutralizing antibody. J. Mol. Biol. 382, 942–955 (2008).

  21. 21.

    et al. Charged residues dominate a unique interlocking topography in the heterodimeric cytokine interleukin-12. EMBO J. 19, 3530–3541 (2000).

  22. 22.

    , , , & Distinct subunit pairing criteria within the heterodimeric IL-12 cytokine family. Mol. Immunol. 51, 234–244 (2012).

  23. 23.

    et al. A role for IL-27p28 as an antagonist of gp130-mediated signaling. Nat. Immunol. 11, 1119–1126 (2010). This study provides one of the first clear indications that single-chain components of the IL-12 cytokine family can act as competitive inhibitors.

  24. 24.

    & IL-12p40: an inherently agonistic cytokine. Trends Immunol. 28, 33–38 (2007).

  25. 25.

    et al. Interleukin 12p40 is required for dendritic cell migration and T cell priming after Mycobacterium tuberculosis infection. J. Exp. Med. 203, 1805–1815 (2006).

  26. 26.

    et al. Interleukin-12 antagonist activity of mouse interleukin-12 p40 homodimer in vitro and in vivo. Ann. NY Acad. Sci. 795, 1–12 (1996).

  27. 27.

    et al. Mouse interleukin-12 (IL-12) p40 homodimer: a potent IL-12 antagonist. Eur. J. Immunol. 25, 200–206 (1995).

  28. 28.

    , & Interpreting mixed signals: the cell's cytokine conundrum. Curr. Opin. Immunol. 23, 632–638 (2011).

  29. 29.

    et al. The composition and signaling of the IL-35 receptor are unconventional. Nat. Immunol. 13, 290–299 (2012).In this study, two unique and unusual aspects of IL-35 signaling are identified: first, that IL-35 can signal via three receptors (IL-12Rβ2–gp130, IL-12Rβ2–IL-12Rβ2 and gp130-gp130); and second, that IL-35 mediates part of its inhibitory program via STAT1-STAT4 heterodimers.

  30. 30.

    , , & Structural biology of shared cytokine receptors. Annu. Rev. Immunol. 27, 29–60 (2009).

  31. 31.

    et al. Molecular mechanisms for viral mimicry of a human cytokine: activation of gp130 by HHV-8 interleukin-6. J. Mol. Biol. 335, 641–654 (2004).

  32. 32.

    , , & Hexameric structure and assembly of the interleukin-6/IL-6 α-receptor/gp130 complex. Science 300, 2101–2104 (2003).

  33. 33.

    , , , & Developmental commitment to the Th2 lineage by extinction of IL-12 signaling. Immunity 2, 665–675 (1995).

  34. 34.

    , , & Regulation of the interleukin (IL)-12Rβ2 subunit expression in developing T helper 1 (Th1) and Th2 cells. J. Exp. Med. 185, 817–824 (1997).

  35. 35.

    et al. Selective expression of an interleukin-12 receptor component by human T helper 1 cells. J. Exp. Med. 185, 825–831 (1997).

  36. 36.

    & Regulation of interleukin-12 production in antigen-presenting cells. Adv. Immunol. 79, 55–92 (2001).

  37. 37.

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

  38. 38.

    et al. Helper T cell IL-2 production is limited by negative feedback and STAT-dependent cytokine signals. J. Exp. Med. 204, 65–71 (2007).

  39. 39.

    , , , & WSX-1: a key role in induction of chronic intestinal nematode infection. J. Immunol. 172, 7635–7641 (2004).

  40. 40.

    et al. Positive and negative regulation of the IL-27 receptor during lymphoid cell activation. J. Immunol. 174, 7684–7691 (2005).

  41. 41.

    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).

  42. 42.

    et al. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat. Immunol. 8, 1363–1371 (2007).

  43. 43.

    et al. Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells. Nat. Immunol. 8, 1372–1379 (2007).

  44. 44.

    et al. A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat. Immunol. 8, 1380–1389 (2007). The studies in references 42–44 show for the first time that IL-27 can induce IL-10 production and facilitate the development of Tr1 cells.

  45. 45.

    et al. Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J. Immunol. 183, 797–801 (2009).

  46. 46.

    et al. IL-27 blocks RORc expression to inhibit lineage commitment of Th17 cells. J. Immunol. 182, 5748–5756 (2009).

  47. 47.

    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).The study in reference 47, along with those in references 45 and 49, show that the IL-27-induced Tr1 program is driven by a c-Maf–AhR axis.

  48. 48.

    , & Identification of an IL-27/osteopontin axis in dendritic cells and its modulation by IFN-gamma limits IL-17-mediated autoimmune inflammation. Proc. Natl. Acad. Sci. USA 107, 11495–11500 (2010).

  49. 49.

    et al. Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3+ regulatory T cells. Nat. Immunol. 11, 846–853 (2010).

  50. 50.

    et al. A functional interleukin 12 receptor complex is composed of two β-type cytokine receptor subunits. Proc. Natl. Acad. Sci. USA 93, 14002–14007 (1996).

  51. 51.

    et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450, 566–569 (2007). This study was the first to show that IL-35 is an inhibitory cytokine made by nTreg cells, which is required for their maximal inhibitory activity.

  52. 52.

    , , & Regulatory T cell suppression is potentiated by target T cells in a cell contact, IL-35- and IL-10-dependent manner. J. Immunol. 182, 6121–6128 (2009).

  53. 53.

    et al. IL-35-mediated induction of a potent regulatory T cell population. Nat. Immunol. 11, 1093–1101 (2010). This study shows that that IL-35 can induce the development of a peripheral Treg cell population, iTr35 cells, which also effect suppression via IL-35. The iTr35 cells can be induced by nTreg cells in inflammatory sites and contribute to infectious tolerance.

  54. 54.

    et al. γδ T cells enhance autoimmunity by restraining regulatory T cell responses via an interleukin-23-dependent mechanism. Immunity 33, 351–363 (2010).

  55. 55.

    , , & A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6, 1142–1151 (2005).

  56. 56.

    & Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat. Immunol. 6, 1152–1159 (2005).

  57. 57.

    et al. IL-27 limits IL-2 production during Th1 differentiation. J. Immunol. 176, 237–247 (2006).

  58. 58.

    , & Interleukin-12 differentially regulates expression of IFN-γ and interleukin-2 in human T lymphoblasts. J. Interferon Cytokine Res. 20, 897–905 (2000).

  59. 59.

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

  60. 60.

    et al. IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells. Eur. J. Immunol. 37, 3021–3029 (2007).

  61. 61.

    et al. IL-35, an anti-inflammatory cytokine which expands CD4+CD25+ Treg Cells. J. Biol. Regul. Homeost. Agents 24, 131–135 (2010).

  62. 62.

    et al. Cutting edge: IL-27 is a potent inducer of IL-10 but not FoxP3 in murine T cells. J. Immunol. 180, 2752–2756 (2008).

  63. 63.

    , , , & Cutting edge: human regulatory T cells require IL-35 to mediate suppression and infectious tolerance. J. Immunol. 186, 6661–6666 (2011).

  64. 64.

    et al. Control of T helper cell differentiation through cytokine receptor inclusion in the immunological synapse. J. Exp. Med. 206, 877–892 (2009).

  65. 65.

    , , & A role for the immunological synapse in lineage commitment of CD4 lymphocytes. Nature 431, 527–532 (2004).

  66. 66.

    et al. Differential distribution of both IL-12Rβ chains in the plasma membrane of human T cells. J. Membr. Biol. 227, 1–12 (2009).

  67. 67.

    STATs: signal transducers and activators of transcription. Cell 84, 331–334 (1996).

  68. 68.

    & Serine phosphorylation of STATs. Oncogene 19, 2628–2637 (2000).

  69. 69.

    & Transcription factor activity of STAT proteins: structural requirements and regulation by phosphorylation and interacting proteins. Cell Mol. Life Sci. 55, 1535–1546 (1999).

  70. 70.

    & Role of STAT3 in type I interferon responses. Negative regulation of STAT1-dependent inflammatory gene activation. J. Biol. Chem. 281, 14111–14118 (2006).

  71. 71.

    et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13, 715–725 (2000).

  72. 72.

    et al. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J. Exp. Med. 170, 827–845 (1989).

  73. 73.

    et al. Expression cloning of a human IL-12 receptor component. A new member of the cytokine receptor superfamily with strong homology to gp130. J. Immunol. 153, 128–136 (1994).

  74. 74.

    , , & Cloning and characterization of a mouse IL-12 receptor-β component. J. Immunol. 155, 4286–4294 (1995).

  75. 75.

    et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R. J. Immunol. 168, 5699–5708 (2002).

  76. 76.

    et al. WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. J. Immunol. 172, 2225–2231 (2004).

  77. 77.

    The Janus protein tyrosine kinase family and its role in cytokine signaling. Adv. Immunol. 60, 1–35 (1995).

  78. 78.

    , & Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell 109 (suppl.), S121–S131 (2002).

  79. 79.

    et al. Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 382, 171–174 (1996).

  80. 80.

    , , & IL-27 regulates IL-12 responsiveness of naive CD4+ T cells through Stat1-dependent and -independent mechanisms. Proc. Natl. Acad. Sci. USA 100, 15047–15052 (2003).

  81. 81.

    , , & IL-27 and IFN-α signal via Stat1 and Stat3 and induce T-bet and IL-12Rβ2 in naive T cells. J. Interferon Cytokine Res. 23, 513–522 (2003).

  82. 82.

    & Regulation of TH1 differentiation–controlling the controllers. Nat. Immunol. 3, 506–508 (2002).

  83. 83.

    New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nat. Rev. Immunol. 5, 521–531 (2005).

  84. 84.

    et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006). This study shows that IL-23 can facilitate the development of TH17 cells.

  85. 85.

    et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J. Exp. Med. 198, 1951–1957 (2003).

  86. 86.

    et al. IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells. J. Exp. Med. 207, 2895–2906 (2010).

  87. 87.

    , & 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).

  88. 88.

    et al. IL-27 synthesis induced by TLR ligation critically depends on IFN regulatory factor 3. J. Immunol. 178, 7607–7615 (2007).

  89. 89.

    et al. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nat. Immunol. 10, 167–175 (2009).

  90. 90.

    , , , & Prevention of Autoimmune Diabetes by Ectopic Pancreatic beta-Cell Expression of Interleukin-35. Diabetes 61, 1519–1526 (2009).

  91. 91.

    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).

  92. 92.

    et al. IL-35 production by inducible costimulator (ICOS)-positive regulatory T cells reverses established IL-17-dependent allergic airways disease. J. Allergy Clin. Immunol. 129, 207–215 (2012).

  93. 93.

    , , & Detectable expression of IL-35 in CD4+ T cells from peripheral blood of chronic hepatitis B patients. Clin. Immunol. 139, 1–5 (2011).

  94. 94.

    , , , & Interleukin-35 mediates mucosal immune responses that protect against T-cell-dependent colitis. Gastroenterology 141, 1875–1886 (2011).

  95. 95.

    , , , & 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).

  96. 96.

    et al. Airway inflammation and IgE production induced by dust mite allergen-specific memory/effector Th2 cell line can be effectively attenuated by IL-35. J. Immunol. 187, 462–471 (2011).

  97. 97.

    , , , & Interleukin-35 enhances Lyme arthritis in Borrelia-vaccinated and -infected mice. Clin. Vaccine Immunol. 18, 1125–1132 (2011).

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Acknowledgements

Supported by the US National Institutes of Health (AI091977 to D.A.A.V., and NS30843 to V.K.K.), the National Cancer Institute (CA21765 to D.A.A.V.), the American Asthma Foundation (10-0128 to D.A.A.V.) and the American Lebanese Syrian Associated Charities (D.A.A.V.).

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  1. Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

    • Dario A A Vignali
  2. Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Vijay K Kuchroo

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Competing interests

D.A.A.V. has submitted patents related to IL-35 that are pending and is entitled to a share in net income generated from licensing of those patent rights for commercial development.

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Correspondence to Dario A A Vignali.

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https://doi.org/10.1038/ni.2366

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