The IL-23–IL-17 immune axis: from mechanisms to therapeutic testing (original) (raw)

• Cua, D. J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003). This study shows that IL-23 controls a key checkpoint for the induction of autoimmune inflammation.
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Langrish, C. L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005). This is the first study to suggest that IL-17-producing cells are crucial mediators of autoimmunity, and it led to the proposal of the T H 17 hypothesis.
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Harrington, L. E. et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nature Immunol. 6, 1123–1132 (2005). This study coined the term 'T H 17' cells to describe a unique lineage that is STAT3 dependent, rather than STAT4- and STAT6-independent.
  Article CAS Google Scholar
• Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nature Immunol. 6, 1133–1141 (2005). This is one of the first papers suggesting the existence of IL-17-producing inflammatory T cells.
  Article CAS Google Scholar
• Mosmann, T. R., Cherwinski, H., Bond, M. W., Giedlin, M. A. & Coffman, R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol. 136, 2348–2357 (1986). This is the landmark paper proposing the T H 1–T H 2 hypothesis.
  CAS PubMed Google Scholar
• Mosmann, T. R. & Coffman, R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145–173 (1989).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Weaver, C. T., Hatton, R. D., Mangan, P. R. & Harrington, L. E. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu. Rev. Immunol. 25, 821–852 (2007).
  Article CAS PubMed Google Scholar
• Ivanov, I. I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006). This study describes the discovery of a novel transcriptional regulator that controls Il17a expression and provides the definitive proof that T H 17 cells belong to a new lineage of CD4+ T H cells.
  Article CAS PubMed Google Scholar
• Cua, D. J. & Tato, C. M. Innate IL-17-producing cells: the sentinels of the immune system. Nature Rev. Immunol. 10, 479–489 (2010).
  Article CAS Google Scholar
• Annunziato, F., Cosmi, L., Liotta, F., Maggi, E. & Romagnani, S. Type 17 T helper cells—origins, features and possible roles in rheumatic disease. Nature Rev. Rheumatol. 5, 325–331 (2009).
  Article CAS Google Scholar
• Zuniga, L. A., Jain, R., Haines, C. & Cua, D. J. Th17 cell development: from the cradle to the grave. Immunol. Rev. 252, 78–88 (2013).
  Article CAS PubMed Google Scholar
• Kim, J. S. et al. Natural and inducible TH17 cells are regulated differently by Akt and mTOR pathways. Nature Immunol. 14, 611–618 (2013).
  Article CAS Google Scholar
• Marks, B. R. et al. Thymic self-reactivity selects natural interleukin 17-producing T cells that can regulate peripheral inflammation. Nature Immunol. 10, 1125–1132 (2009).
  Article CAS Google Scholar
• Zheng, Y. et al. Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445, 648–651 (2007).
  Article CAS PubMed Google Scholar
• El-Behi, M. et al. The encephalitogenicity of TH17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nature Immunol. 12, 568–575 (2011).
  Article CAS Google Scholar
• Codarri, L. et al. RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nature Immunol. 12, 560–567 (2011).
  Article CAS Google Scholar
• McGeachy, M. J. et al. TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell-mediated pathology. Nature Immunol. 8, 1390–1397 (2007).
  Article CAS Google Scholar
• Hirota, K. et al. Plasticity of Th17 cells in Peyer's patches is responsible for the induction of T cell-dependent IgA responses. Nature Immunol. 14, 372–379 (2013).
  Article CAS Google Scholar
• Esplugues, E. et al. Control of TH17 cells occurs in the small intestine. Nature 475, 514–518 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Chackerian, A. A. et al. Neutralization or absence of the interleukin-23 pathway does not compromise immunity to mycobacterial infection. Infect. Immun. 74, 6092–6099 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Chen, Y. et al. Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J. Clin. Invest. 116, 1317–1326 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Lieberman, L. A. et al. IL-23 provides a limited mechanism of resistance to acute toxoplasmosis in the absence of IL-12. J. Immunol. 173, 1887–1893 (2004).
  Article CAS PubMed Google Scholar
• Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).
  Article CAS PubMed Google Scholar
• Mangan, P. R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).
  Article CAS PubMed Google Scholar
• Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006). References 27–29 show the importance of TGFβ plus IL-6 in the lineage specification of T H 17 cells.
  Article CAS PubMed Google Scholar
• Yang, X. O. et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J. Biol. Chem. 282, 9358–9363 (2007).
  Article CAS PubMed Google Scholar
• Durant, L. et al. Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity 32, 605–615 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Samoilova, E. B., Horton, J. L., Hilliard, B., Liu, T. S. & Chen, Y. IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: roles of IL-6 in the activation and differentiation of autoreactive T cells. J. Immunol. 161, 6480–6486 (1998).
  CAS PubMed Google Scholar
• Alonzi, T. et al. Interleukin 6 is required for the development of collagen-induced arthritis. J. Exp. Med. 187, 461–468 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Korn, T. et al. IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 448, 484–487 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Nurieva, R. et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448, 480–483 (2007).
  Article CAS PubMed Google Scholar
• Spolski, R. & Leonard, W. J. The Yin and Yang of interleukin-21 in allergy, autoimmunity and cancer. Curr. Opin. Immunol. 20, 295–301 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Sutton, C., Brereton, C., Keogh, B., Mills, K. H. & Lavelle, E. C. A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. J. Exp. Med. 203, 1685–1691 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Chung, Y. et al. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30, 576–587 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Gulen, M. F. et al. The receptor SIGIRR suppresses Th17 cell proliferation via inhibition of the interleukin-1 receptor pathway and mTOR kinase activation. Immunity 32, 54–66 (2010). This paper shows that IL-1 is a key factor that provides a key competitive advantage for in vivo T H 17 cell expansion and survival during inflammatory conditions by inducing catabolic energy pathways.
  Article CAS PubMed PubMed Central Google Scholar
• Veldhoen, M., Hocking, R. J., Flavell, R. A. & Stockinger, B. Signals mediated by transforming growth factor-β initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nature Immunol. 7, 1151–1156 (2006).
  Article CAS Google Scholar
• Li, M. O., Wan, Y. Y. & Flavell, R. A. T cell-produced transforming growth factor-β1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity 26, 579–591 (2007).
  Article CAS PubMed Google Scholar
• Gutcher, I. et al. Autocrine transforming growth factor-β1 promotes in vivo Th17 cell differentiation. Immunity 34, 396–408.
  Article CAS PubMed PubMed Central Google Scholar
• Das, J. et al. Transforming growth factor β is dispensable for the molecular orchestration of Th17 cell differentiation. J. Exp. Med. 206, 2407–2416 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Volpe, E. et al. A critical function for transforming growth factor-β, interleukin 23 and proinflammatory cytokines in driving and modulating human TH-17 responses. Nature Immunol. 9, 650–657 (2008).
  Article CAS Google Scholar
• Manel, N., Unutmaz, D. & Littman, D. R. The differentiation of human TH-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt. Nature Immunol. 9, 641–649 (2008).
  Article CAS Google Scholar
• Acosta-Rodriguez, E. V., Napolitani, G., Lanzavecchia, A. & Sallusto, F. Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17-producing human T helper cells. Nature Immunol. 8, 942–949 (2007).
  Article CAS Google Scholar
• Wilson, N. J. et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nature Immunol. 8, 950–957 (2007).
  Article CAS Google Scholar
• Chen, Z., Tato, C. M., Muul, L., Laurence, A. & O'Shea, J. J. Distinct regulation of interleukin-17 in human T helper lymphocytes. Arthritis Rheum. 56, 2936–2946 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Yang, Y. et al. T-bet is essential for encephalitogenicity of both Th1 and Th17 cells. J. Exp. Med. 206, 1549–1564 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Jager, A., Dardalhon, V., Sobel, R. A., Bettelli, E. & Kuchroo, V. K. Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J. Immunol. 183, 7169–7177 (2009).
  Article CAS PubMed Google Scholar
• McGeachy, M. J. et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nature Immunol. 10, 314–324 (2009). This paper describes the crucial roles of IL-23 for the in vivo expansion and function of T H 17 cells during inflammation.
  Article CAS Google Scholar
• Haines, C. J. et al. Autoimmune memory T helper 17 cell function and expansion are dependent on interleukin-23. Cell Rep. 3, 1378–1388 (2013).
  Article CAS PubMed Google Scholar
• Ghoreschi, K. et al. Generation of pathogenic TH17 cells in the absence of TGF-β signalling. Nature 467, 967–971 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Kebir, H. et al. Preferential recruitment of interferon-γ-expressing TH17 cells in multiple sclerosis. Ann. Neurol. 66, 390–402 (2009).
  Article CAS PubMed Google Scholar
• Hirota, K. et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nature Immunol. 12, 255–263 (2011). This elegant study used an Il17a fate-mapping strategy to demonstrate the existence of “ex-T H 17” cells driving autoimmune pathology.
  Article CAS Google Scholar
• Lee, Y. et al. Induction and molecular signature of pathogenic TH17 cells. Nature Immunol. 13, 991–999 (2012).
  Article CAS Google Scholar
• Duerr, R. H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Liu, Y. et al. A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet. 4, e1000041 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Reveille, J. D. et al. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nature Genet. 42, 123–127 (2010).
  Article CAS PubMed Google Scholar
• Lock, C. et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nature Med. 8, 500–508 (2002).
  Article CAS PubMed Google Scholar
• Burton, P. R. et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nature Genet. 39, 1329–1337 (2007).
  Article CAS PubMed Google Scholar
• Ghoreschi, K. et al. Generation of pathogenic TH17 cells in the absence of TGF-β signalling. Nature 467, 967–971 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Diveu, C. et al. IL-27 blocks RORc expression to inhibit lineage commitment of Th17 cells. J. Immunol. 182, 5748–5756 (2009). This study shows that IL-27 is an inhibitor of the T H 17 immune pathway and explores the mechanisms underlying IL-27-mediated regulation of inflammation.
  Article CAS PubMed Google Scholar
• Laurence, A. et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26, 371–381 (2007).
  Article CAS PubMed Google Scholar
• El-behi, M. et al. Differential effect of IL-27 on developing versus committed Th17 cells. J. Immunol. 183, 4957–4967 (2009).
  Article CAS PubMed Google Scholar
• Veldhoen, M. et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008).
  Article CAS PubMed Google Scholar
• Quintana, F. J. et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453, 65–71 (2008).
  Article CAS PubMed Google Scholar
• 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. Nature Immunol. 11, 854–861 (2010).
  Article CAS Google Scholar
• Milner, J. D. et al. Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452, 773–776 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Minegishi, Y. et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 448, 1058–1062 (2007).
  Article CAS PubMed Google Scholar
• Ise, W. et al. The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells. Nature Immunol. 12, 536–543 (2011).
  Article CAS Google Scholar
• Schraml, B. U. et al. The AP-1 transcription factor Batf controls TH17 differentiation. Nature 460, 405–409 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Lohoff, M. et al. Dysregulated T helper cell differentiation in the absence of interferon regulatory factor 4. Proc. Natl Acad. Sci. USA 99, 11808–11812 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Brustle, A. et al. The development of inflammatory TH-17 cells requires interferon-regulatory factor 4. Nature Immunol. 8, 958–966 (2007).
  Article CAS Google Scholar
• Li, P. et al. BATF–JUN is critical for IRF4-mediated transcription in T cells. Nature 490, 543–546 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Ciofani, M. et al. A validated regulatory network for Th17 cell specification. Cell 151, 289–303 (2012). This study argues against the hypothesis that RORγt is the only factor that regulates the specification of the T H 17 lineage.
  Article CAS PubMed PubMed Central Google Scholar
• Oestreich, K. J. & Weinmann, A. S. Master regulators or lineage-specifying? Changing views on CD4+ T cell transcription factors. Nature Rev. Immunol. 12, 799–804 (2012).
  Article CAS Google Scholar
• Vahedi, G. et al. STATs shape the active enhancer landscape of T cell populations. Cell 151, 981–993 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Samstein, R. M. et al. Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell 151, 153–166 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Dang, E. V. et al. Control of TH17/Treg balance by hypoxia-inducible factor 1. Cell 146, 772–784 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Chen, Z. et al. The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. Immunity 39, 272–285 (2013).
  Article CAS PubMed Google Scholar
• van Loosdregt, J. et al. Stabilization of the transcription factor Foxp3 by the deubiquitinase USP7 increases Treg-cell-suppressive capacity. Immunity 39, 259–271 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Yang, X. O. et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 29, 44–56 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Wei, G. et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30, 155–167 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Lee, Y. K. et al. Late developmental plasticity in the T helper 17 lineage. Immunity 30, 92–107 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Morrison, P. J. et al. Th17-cell plasticity in Helicobacter hepaticus-induced intestinal inflammation. Mucosal Immunol. 6, 1143–1156 (2013).
  Article CAS PubMed Google Scholar
• Iwakura, Y., Ishigame, H., Saijo, S. & Nakae, S. Functional specialization of interleukin-17 family members. Immunity 34, 149–162 (2011).
  Article CAS PubMed Google Scholar
• Onishi, R. & Gaffen, S. L. IL-17 and its target genes: mechanisms of IL-17 function in disease. Immunology 129, 311–321 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Yao, Z. et al. Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 3, 811–821 (1995).
  Article CAS PubMed Google Scholar
• Ishigame, H. et al. Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity 30, 108–119 (2009).
  Article CAS PubMed Google Scholar
• Novatchkova, M., Leibbrandt, A., Werzowa, J., Neubuser, A. & Eisenhaber, F. The STIR-domain superfamily in signal transduction, development and immunity. Trends Biochem. Sci. 28, 226–229 (2003).
  Article CAS PubMed Google Scholar
• Rickel, E. A. et al. Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities. J. Immunol. 181, 4299–4310 (2008).
  Article CAS PubMed Google Scholar
• Bordon, Y. Cytokines: IL-17C joins the family firm. Nature Rev. Immunol. 11, 805 (2011).
  CAS Google Scholar
• Qian, Y. et al. The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nature Immunol. 8, 247–256 (2007).
  Article CAS Google Scholar
• Chang, S. H., Park, H. & Dong, C. Act1 adaptor protein is an immediate and essential signaling component of interleukin-17 receptor. J. Biol. Chem. 281, 35603–35607 (2006).
  Article CAS PubMed Google Scholar
• Li, X. Act1 modulates autoimmunity through its dual functions in CD40L/BAFF and IL-17 signaling. Cytokine 41, 105–113 (2008).
  Article CAS PubMed Google Scholar
• Liu, C. et al. Act1, a U-box E3 ubiquitin ligase for IL-17 signaling. Sci. Signal. 2, ra63 (2009).
  PubMed PubMed Central Google Scholar
• Schwandner, R., Yamaguchi, K. & Cao, Z. Requirement of tumor necrosis factor-associated factor (TRAF)6 in interleukin 17 signal transduction. J. Exp. Med. 191, 1233–1239 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Sun, D. et al. Treatment with IL-17 prolongs the half-life of chemokine CXCL1 mRNA via the adaptor TRAF5 and the splicing-regulatory factor SF2 (ASF). Nature Immunol. 12, 853–860 (2011).
  Article CAS Google Scholar
• Herjan, T. et al. HuR is required for IL-17-induced Act1-mediated CXCL1 and CXCL5 mRNA stabilization. J. Immunol. 191, 640–649 (2013).
  Article CAS PubMed Google Scholar
• Bulek, K. et al. The inducible kinase IKKi is required for IL-17-dependent signaling associated with neutrophilia and pulmonary inflammation. Nature Immunol. 12, 844–852 (2011).
  Article CAS Google Scholar
• Qu, F. et al. TRAF6-dependent Act1 phosphorylation by the IκB kinase-related kinases suppresses interleukin-17-induced NF-κB activation. Mol. Cell. Biol. 32, 3925–3937 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, C. et al. The psoriasis-associated D10N variant of the adaptor Act1 with impaired regulation by the molecular chaperone hsp90. Nature Immunol. 14, 72–81 (2013).
  Article CAS Google Scholar
• Sonder, S. U. et al. IL-17-induced NF-κB activation via CIKS/Act1: physiologic significance and signaling mechanisms. J. Biol. Chem. 286, 12881–12890 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Huffmeier, U. et al. Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis. Nature Genet. 42, 996–999 (2010).
  Article CAS PubMed Google Scholar
• Shen, F., Ruddy, M. J., Plamondon, P. & Gaffen, S. L. Cytokines link osteoblasts and inflammation: microarray analysis of interleukin-17- and TNF-α-induced genes in bone cells. J. Leukoc. Biol. 77, 388–399 (2005).
  Article CAS PubMed Google Scholar
• Acosta-Rodriguez, E. V. et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nature Immunol. 8, 639–646 (2007).
  Article CAS Google Scholar
• Yang, D. et al. β-Defensins: Linking innate immunity and adaptive immunity through dendritic and T cell CCR6. Science 286, 525–528 (1999).
  Article CAS PubMed Google Scholar
• Goetz, D. H. et al. The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol. Cell 10, 1033–1043 (2002).
  Article CAS PubMed Google Scholar
• Ruddy, M. J. et al. Functional cooperation between interleukin-17 and tumor necrosis factor-a is mediated by CCAAT/enhancer binding protein family members. J. Biol. Chem. 279, 2559–2567 (2004).
  Article CAS PubMed Google Scholar
• Shen, F., Hu, Z., Goswami, J. & Gaffen, S. L. Identification of common transcriptional regulatory elements in interleukin-17 target genes. J. Biol. Chem. 281, 24138–24148 (2006).
  Article CAS PubMed Google Scholar
• Patel, D. N. et al. Interleukin-17 stimulates C-reactive protein expression in hepatocytes and smooth muscle cells via p38 MAPK and ERK1/2-dependent NF-κB and C/EBPβ activation. J. Biol. Chem. 282, 27229–27238 (2007).
  Article CAS PubMed Google Scholar
• Ramji, D. P. & Foka, P. CCAAT/enhancer-binding proteins: structure, function and regulation. Biochem. J. 365, 561–575 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Shen, F. et al. IL-17 receptor signaling inhibits C/EBPβ by sequential phosphorylation of the regulatory 2 domain. Sci. Signal. 2, ra8 (2009).
  Article PubMed PubMed Central Google Scholar
• Zrioual, S. et al. Genome-wide comparison between IL-17A- and IL-17F-induced effects in human rheumatoid arthritis synoviocytes. J. Immunol. 182, 3112–3120 (2009).
  Article CAS PubMed Google Scholar
• Shen, F. & Gaffen, S. L. Structure–function relationships in the IL-17 receptor: Implications for signal transduction and therapy. Cytokine 41, 92–104 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Karlsen, J. R., Borregaard, N. & Cowland, J. B. Induction of neutrophil gelatinase-associated lipocalin expression by co-stimulation with interleukin-17 and tumor necrosis factor-α is controlled by IκB-ζ but neither by C/EBP-β nor C/EBP-δ. J. Biol. Chem. 285, 14088–14100 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Zhong, B. et al. Negative regulation of IL-17-mediated signaling and inflammation by the ubiquitin-specific protease USP25. Nature Immunol. 13, 1110–1117 (2012).
  Article CAS Google Scholar
• Garg, A. V., Ahmed, M., Vallejo, A. N., Ma, A. & Gaffen, S. L. The deubiquitinase A20 mediates feedback inhibition of interleukin-17 receptor signaling. Sci. Signal. 6, ra44 (2013). References 118 and 119 show that IL-17R signalling is restrained by multiple deubiquitylating enzymes that target TRAF6.
  Article CAS PubMed PubMed Central Google Scholar
• Ma, A. & Malynn, B. A. A20: linking a complex regulator of ubiquitylation to immunity and human disease. Nature Rev. Immunol. 12, 774–785 (2012).
  Article CAS Google Scholar
• Zhu, S. et al. Modulation of experimental autoimmune encephalomyelitis through TRAF3-mediated suppression of interleukin 17 receptor signaling. J. Exp. Med. 207, 2647–2662 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Maitra, A. et al. Distinct functional motifs within the IL-17 receptor regulate signal transduction and target gene expression. Proc. Natl Acad. Sci, USA 104, 7506–7511 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Shembade, N. & Harhaj, E. W. Regulation of NF-κB signaling by the A20 deubiquitinase. Cell. Mol. Immunol. 9, 123–130 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Iha, H. et al. Inflammatory cardiac valvulitis in TAX1BP1-deficient mice through selective NF-κB activation. EMBO J. 27, 629–641 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Shembade, N. et al. The E3 ligase Itch negatively regulates inflammatory signaling pathways by controlling the function of the ubiquitin-editing enzyme A20. Nature Immunol. 9, 254–262 (2008).
  Article CAS Google Scholar
• Garg, A. V. & Gaffen, S. L. IL-17 signaling and A20: a balancing act. Cell Cycle 12, 3459–3460 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Ho, A. W. et al. The anaphase-promoting complex protein 5 (AnapC5) associates with A20 and inhibits IL-17-mediated signal transduction. PLoS ONE 8, e70168 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Shi, P. et al. Persistent stimulation with interleukin-17 desensitizes cells through SCFβ-TrCP-mediated degradation of Act1. Sci. Signal. 4, ra73 (2011).
  Article CAS PubMed Google Scholar
• Xie, P. TRAF molecules in cell signaling and in human diseases. J. Mol. Signal 8, 1–31 (2013).
  Article CAS Google Scholar
• Zepp, J. A. et al. Cutting edge: TNF receptor-associated factor 4 restricts IL-17-mediated pathology and signaling processes. J. Immunol. 189, 33–37 (2012).
  Article CAS PubMed Google Scholar
• O'Connell, R. M. et al. MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity 33, 607–619 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Yao, R. et al. MicroRNA-155 modulates Treg and Th17 cells differentiation and Th17 cell function by targeting SOCS1. PLoS ONE 7, e46082 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Murugaiyan, G., Beynon, V., Mittal, A., Joller, N. & Weiner, H. L. Silencing microRNA-155 ameliorates experimental autoimmune encephalomyelitis. J. Immunol. 187, 2213–2221 (2011).
  Article CAS PubMed Google Scholar
• Zhu, S. et al. The microRNA miR-23b suppresses IL-17-associated autoimmune inflammation by targeting TAB2, TAB3 and IKK-α. Nature Med. 18, 1077–1086 (2012). This is the first identification of an miRNA feedback loop in the IL-17R signalling pathway.
  Article CAS PubMed Google Scholar
• Milner, J. D. & Holland, S. M. The cup runneth over: lessons from the ever-expanding pool of primary immunodeficiency diseases. Nature Rev. Immunol. 13, 635–648 (2013).
  Article CAS Google Scholar
• von Bernuth, H. et al. Pyogenic bacterial infections in humans with MyD88 deficiency. Science 321, 691–696 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Ma, C. S. et al. Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J. Exp. Med. 205, 1551–1557 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Glocker, E. O. et al. A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N. Engl. J. Med. 361, 1727–1735 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Liu, L. et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J. Exp. Med. 208, 1635–1648 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• van de Veerdonk, F. L. et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N. Engl. J. Med. 365, 54–61 (2011).
  Article CAS PubMed Google Scholar
• Puel, A. et al. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J. Exp. Med. 207, 291–297 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Kisand, K. et al. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J. Exp. Med. 207, 299–308 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Puel, A. et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 332, 65–68 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Boisson, B. et al. A biallelic ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidiasis. Immunity 39, 676–686 (2013). References 143 and 144 directly link mucosal C. albicans infections with the IL-17R-mediated signalling axis.
  Article CAS PubMed Google Scholar
• Hernández-Santos, N. & Gaffen, S. L. Th17 cells in immunity to Candida albicans. Cell Host Microbe 11, 425–435 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Stark, M. A. et al. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity 22, 285–294 (2005).
  Article CAS PubMed Google Scholar
• Sherlock, J. P. et al. IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4−CD8− entheseal resident T cells. Nature Med. 18, 1069–1076 (2012).
  Article CAS PubMed Google Scholar
• Chan, J. R. et al. IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J. Exp. Med. 203, 2577–2587 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Tonel, G. et al. Cutting edge: A critical functional role for IL-23 in psoriasis. J. Immunol. 185, 5688–5691 (2010).
  Article CAS PubMed Google Scholar
• Perera, G. K., Di Meglio, P. & Nestle, F. O. Psoriasis. Annu. Rev. Pathol. 7, 385–422 (2012).
  Article CAS PubMed Google Scholar
• Villanova, F. et al. Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis. J. Invest. Dermatol. 134, 984–991 (2014).
  Article CAS PubMed Google Scholar
• Guttman-Yassky, E. et al. Low expression of the IL-23/Th17 pathway in atopic dermatitis compared to psoriasis. J. Immunol. 181, 7420–7427 (2008).
  Article CAS PubMed Google Scholar
• Rudwaleit, M. et al. The Assessment of SpondyloArthritis International Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general. Ann. Rheum. Dis. 70, 25–31 (2011).
  Article CAS PubMed Google Scholar
• van Echteld, I. et al. Identification of the most common problems by patients with ankylosing spondylitis using the international classification of functioning, disability and health. J. Rheumatol 33, 2475–2483 (2006).
  PubMed Google Scholar
• Mielants, H. et al. The evolution of spondyloarthropathies in relation to gut histology. II. Histological aspects. J. Rheumatol 22, 2273–2278 (1995).
  CAS PubMed Google Scholar
• Cotterill, L. et al. Replication and meta-analysis of 13,000 cases defines the risk for interleukin-23 receptor and autophagy-related 16-like 1 variants in Crohn's disease. Can. J. Gastroenterol. 24, 297–302 (2010).
  Article PubMed PubMed Central Google Scholar
• Lesage, S. et al. CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. Am. J. Hum. Genet. 70, 845–857 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Fujino, S. et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut 52, 65–70 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Dige, A. et al. Increased levels of circulating Th17 cells in quiescent versus active Crohn's disease. J. Crohns Colitis 7, 248–255 (2013).
  Article PubMed Google Scholar
• Leonardi, C. et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N. Engl. J. Med. 366, 1190–1199 (2012).
  Article CAS PubMed Google Scholar
• Rich, P. et al. Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen-finding study. Br. J. Dermatol. 168, 402–411 (2013).
  Article CAS PubMed Google Scholar
• Papp, K. A. et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N. Engl. J. Med. 366, 1181–1189 (2012). References 160–162 report clinical trials that reveal the remarkable efficacy of IL-17- or IL-17RA-specific antibody therapy for the treatment of psoriasis.
  Article CAS PubMed Google Scholar
• Papp, K. A. et al. Dose-dependent improvement in chronic plaque psoriasis following treatment with anti-IL-23p19 humanized monoclonal antibody (MK-3222). Late-breaking Research Symposium. 71st Annual Meeting of the American Academy of Dermatology (2013).
• Chiricozzi, A. & Krueger, J. G. IL-17 targeted therapies for psoriasis. Expert Opin. Investig. Drugs 22, 993–1005 (2013).
  Article CAS PubMed Google Scholar
• Sandborn, W. J. et al. Ustekinumab induction and maintenance therapy in refractory Crohn's disease. N. Engl. J. Med. 367, 1519–1528 (2012).
  Article CAS PubMed Google Scholar
• Hueber, W. et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61, 1693–1700 (2012).
  Article CAS PubMed Google Scholar
• Targan, S. R. et al. A randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and efficacy of AMG 827 in subjects with moderate to severe Crohn's disease. 143, e26 (2012).
• Ogawa, A., Andoh, A., Araki, Y., Bamba, T. & Fujiyama, Y. Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. Clin. Immunol. 110, 55–62 (2004).
  Article CAS PubMed Google Scholar
• Patel, D. D., Lee, D. M., Kolbinger, F. & Antoni, C. Effect of IL-17A blockade with secukinumab in autoimmune diseases. Ann. Rheum. Dis. 72, Suppl. 2, iii116–iii123 (2013).
  Article CAS Google Scholar
• Garber, K. Anti-IL-17 mAbs herald new options in psoriasis. Nature Biotech. 30, 475–477 (2012).
  Article CAS Google Scholar
• Nakamura, R. et al. Tyk2-signaling plays an important role in host defense against Escherichia coli through IL-23-induced IL-17 production by γδ T cells. J. Immunol. 181, 2071–2075 (2008).
  Article CAS PubMed Google Scholar
• Ishizaki, M. et al. Tyk2 is a therapeutic target for psoriasis-like skin inflammation. Int. Immunol. 26, 257–267 (2013).
  Article CAS PubMed Google Scholar
• Solt, L. A. et al. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 472, 491–494 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Huh, J. R. et al. Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity. Nature 472, 486–490 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Xiao, S. et al. Small-molecule RORγt antagonists inhibit T helper 17 Cell transcriptional network by divergent mechanisms. Immunity 40, 477–489 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Lee, J. S. & Cua, D. J. The emerging landscape of RORγt biology. Immunity 40, 451–452 (2014).
  Article CAS PubMed Google Scholar
• Stritesky, G. L., Jameson, S. C. & Hogquist, K. A. Selection of self-reactive T cells in the thymus. Annu. Rev. Immunol. 30, 95–114 (2012).
  Article CAS PubMed Google Scholar
• Kronenberg, M. Toward an understanding of NKT cell biology: progress and paradoxes. Annu. Rev. Immunol. 23, 877–900 (2005).
  Article CAS PubMed Google Scholar
• Spits, H. et al. Innate lymphoid cells—a proposal for uniform nomenclature. Nature Rev. Immunol. 13, 145–149 (2013).
  Article CAS Google Scholar
• Plantinga, T. S. et al. Early stop polymorphism in human DECTIN-1 is associated with increased Candida colonization in hematopoietic stem cell transplant recipients. Clin. Infect. Dis. 49, 724–732 (2009).
  Article CAS PubMed Google Scholar
• Minegishi, Y. et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 25, 745–755 (2006).
  Article CAS PubMed Google Scholar
• Prando, C. et al. Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds. Medicine 92, 109–122 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• de Beaucoudrey, L. et al. Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries. Medicine 89, 381–402 (2010).
  Article CAS PubMed Google Scholar
• Ouederni, M. et al. Clinical features of Candidiasis in patients with inherited interleukin 12 receptor β1 deficiency. Clin. Infect. Dis. 58, 204–213 (2014).
  Article CAS PubMed Google Scholar