Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

IL-12 family cytokines: immunological playmakers

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Architecture of the IL-12 cytokine family.
Figure 2: Interactions between cytokines and their receptors.
Figure 3: The IL-12 family of cytokines as an immunological nexus.

Similar content being viewed by others

References

  1. Collison, L.W. & Vignali, D.A. Interleukin-35: odd one out or part of the family? Immunol. Rev. 226, 248–262 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  4. Kastelein, R.A., Hunter, C.A. & Cua, D.J. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu. Rev. Immunol. 25, 221–242 (2007).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  6. 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 

  7. 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 

  8. Stumhofer, J.S. & Hunter, C.A. Advances in understanding the anti-inflammatory properties of IL-27. Immunol. Lett. 117, 123–130 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Pot, C., Apetoh, L., Awasthi, A. & Kuchroo, V.K. Induction of regulatory Tr1 cells and inhibition of TH17 cells by IL-27. Semin. Immunol. 23, 438–445 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Vignali, D.A.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 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  13. Maloy, K.J. & Kullberg, M.C. IL-23 and Th17 cytokines in intestinal homeostasis. Mucosal Immunol. 1, 339–349 (2008).

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  17. Crabé, S. 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).

    PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Beyer, B.M. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Jones, L.L., Chaturvedi, V., Uyttenhove, C., Van, S.J. & Vignali, D.A. Distinct subunit pairing criteria within the heterodimeric IL-12 cytokine family. Mol. Immunol. 51, 234–244 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Stumhofer, J.S. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Cooper, A.M. & Khader, S.A. IL-12p40: an inherently agonistic cytokine. Trends Immunol. 28, 33–38 (2007).

    CAS  PubMed  Google Scholar 

  25. Khader, S.A. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Gately, M.K. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  28. Delgoffe, G.M., Murray, P.J. & Vignali, D.A. Interpreting mixed signals: the cell's cytokine conundrum. Curr. Opin. Immunol. 23, 632–638 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Collison, L.W. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang, X., Lupardus, P., Laporte, S.L. & Garcia, K.C. Structural biology of shared cytokine receptors. Annu. Rev. Immunol. 27, 29–60 (2009).

    PubMed  PubMed Central  Google Scholar 

  31. Boulanger, M.J. 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).

    CAS  PubMed  Google Scholar 

  32. Boulanger, M.J., Chow, D.C., Brevnova, E.E. & Garcia, K.C. Hexameric structure and assembly of the interleukin-6/IL-6 α-receptor/gp130 complex. Science 300, 2101–2104 (2003).

    CAS  PubMed  Google Scholar 

  33. Szabo, S.J., Jacobson, N.G., Dighe, A.S., Gubler, U. & Murphy, K.M. Developmental commitment to the Th2 lineage by extinction of IL-12 signaling. Immunity 2, 665–675 (1995).

    Article  CAS  PubMed  Google Scholar 

  34. Szabo, S.J., Dighe, A.S., Gubler, U. & Murphy, K.M. Regulation of the interleukin (IL)-12Rβ2 subunit expression in developing T helper 1 (Th1) and Th2 cells. J. Exp. Med. 185, 817–824 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  37. 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 

  38. Villarino, A.V. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bancroft, A.J., Humphreys, N.E., Worthington, J.J., Yoshida, H. & Grencis, R.K. WSX-1: a key role in induction of chronic intestinal nematode infection. J. Immunol. 172, 7635–7641 (2004).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  41. 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 

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

    CAS  PubMed  Google Scholar 

  43. Fitzgerald, D.C. 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).

    CAS  PubMed  Google Scholar 

  44. Awasthi, A. 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.

    CAS  PubMed  Google Scholar 

  45. Pot, C. 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).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  47. 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).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.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Murugaiyan, G., Mittal, A. & Weiner, H.L. 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).

    PubMed  PubMed Central  Google Scholar 

  49. Gandhi, R. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Presky, D.H. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Collison, L.W. 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 nT reg cells, which is required for their maximal inhibitory activity.

    CAS  PubMed  Google Scholar 

  52. Collison, L.W., Pillai, M.R., Chaturvedi, V. & Vignali, D.A. 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).

    CAS  PubMed  Google Scholar 

  53. Collison, L.W. 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 T reg cell population, iTr35 cells, which also effect suppression via IL-35. The iTr35 cells can be induced by nT reg cells in inflammatory sites and contribute to infectious tolerance.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Fontenot, J.D., Rasmussen, J.P., Gavin, M.A. & Rudensky, A.Y. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6, 1142–1151 (2005).

    CAS  PubMed  Google Scholar 

  56. D'Cruz, L.M. & Klein, L. Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat. Immunol. 6, 1152–1159 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  58. Dickensheets, H.L., Freeman, S.L. & Donnelly, R.P. Interleukin-12 differentially regulates expression of IFN-γ and interleukin-2 in human T lymphoblasts. J. Interferon Cytokine Res. 20, 897–905 (2000).

    CAS  PubMed  Google Scholar 

  59. 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 

  60. Niedbala, W. 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).

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  62. Batten, M. 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).

    CAS  PubMed  Google Scholar 

  63. 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 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Maldonado, R.A., Irvine, D.J., Schreiber, R. & Glimcher, L.H. A role for the immunological synapse in lineage commitment of CD4 lymphocytes. Nature 431, 527–532 (2004).

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  68. Decker, T. & Kovarik, P. Serine phosphorylation of STATs. Oncogene 19, 2628–2637 (2000).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  71. Oppmann, B. 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).

    CAS  PubMed  Google Scholar 

  72. Kobayashi, M. 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).

    CAS  PubMed  Google Scholar 

  73. Chua, A.O. 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).

    CAS  PubMed  Google Scholar 

  74. Chua, A.O., Wilkinson, V.L., Presky, D.H. & Gubler, U. Cloning and characterization of a mouse IL-12 receptor-β component. J. Immunol. 155, 4286–4294 (1995).

    CAS  PubMed  Google Scholar 

  75. Parham, C. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  78. O'Shea, J.J., Gadina, M. & Schreiber, R.D. Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell 109 (suppl.), S121–S131 (2002).

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  80. Lucas, S., Ghilardi, N., Li, J. & de Sauvage, F.J. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Hibbert, L., Pflanz, S., de Waal, M.R. & Kastelein, R.A. 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).

    CAS  PubMed  Google Scholar 

  82. O'Shea, J.J. & Paul, W.E. Regulation of TH1 differentiation–controlling the controllers. Nat. Immunol. 3, 506–508 (2002).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  84. Bettelli, E. 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 T H 17 cells.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Batten, M. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 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 

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

    CAS  PubMed  Google Scholar 

  89. Bauquet, A.T. 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).

    CAS  PubMed  Google Scholar 

  90. 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 (2009).

    Google Scholar 

  91. 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 

  92. Whitehead, G.S. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  94. Wirtz, S., Billmeier, U., Mchedlidze, T., Blumberg, R.S. & Neurath, M.F. Interleukin-35 mediates mucosal immune responses that protect against T-cell-dependent colitis. Gastroenterology 141, 1875–1886 (2011).

    CAS  PubMed  Google Scholar 

  95. 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 

  96. Huang, C.H. 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).

    CAS  PubMed  Google Scholar 

  97. Kuo, J., Nardelli, D.T., Warner, T.F., Callister, S.M. & Schell, R.F. Interleukin-35 enhances Lyme arthritis in Borrelia-vaccinated and -infected mice. Clin. Vaccine Immunol. 18, 1125–1132 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

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.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Dario A A Vignali.

Ethics declarations

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.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vignali, D., Kuchroo, V. IL-12 family cytokines: immunological playmakers. Nat Immunol 13, 722–728 (2012). https://doi.org/10.1038/ni.2366

Download citation

  • Published:

  • Issue Date:

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

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing