TH17 cells in development: an updated view of their molecular identity and genetic programming (original) (raw)
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). ArticleCASPubMed Google Scholar
Glimcher, L. H. & Murphy, K. M. Lineage commitment in the immune system: the T helper lymphocyte grows up. Genes Dev.14, 1693–1711 (2000). CASPubMed Google Scholar
Faria, A. M. & Weiner, H. L. Oral tolerance and TGF-β-producing cells. Inflamm. Allergy Drug Targets5, 179–190 (2006). ArticleCASPubMed Google Scholar
Grazia Roncarolo, M. et al. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol. Rev.212, 28–50 (2006). Article Google Scholar
Wing, K., Fehervari, Z. & Sakaguchi, S. Emerging possibilities in the development and function of regulatory T cells. Int. Immunol.18, 991–1000 (2006). ArticleCASPubMed Google Scholar
Vinuesa, C. G., Tangye, S. G., Moser, B. & Mackay, C. R. Follicular B helper T cells in antibody responses and autoimmunity. Nature Rev. Immunol.5, 853–865 (2005). ArticleCAS Google Scholar
Dong, C. Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells. Nature Rev. Immunol.6, 329–334 (2006). ArticleCAS Google Scholar
Harrington, L. E., Mangan, P. R. & Weaver, C. T. Expanding the effector CD4 T-cell repertoire: the TH17 lineage. Curr. Opin. Immunol.18, 349–356 (2006). ArticleCASPubMed Google Scholar
Infante-Duarte, C., Horton, H. F., Byrne, M. C. & Kamradt, T. Microbial lipopeptides induce the production of IL-17 in TH cells. J. Immunol.165, 6107–6115 (2000). ArticleCASPubMed Google Scholar
Dong, C. & Nurieva, R. I. Regulation of immune and autoimmune responses by ICOS. J. Autoimmun.21, 255–260 (2003). ArticlePubMedCAS 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). ArticleCASPubMedPubMed Central 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). ArticleCASPubMedPubMed 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). ArticleCAS 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). ArticleCAS Google Scholar
Kolls, J. K. & Linden, A. Interleukin-17 family members and inflammation. Immunity21, 467–476 (2004). ArticleCASPubMed Google Scholar
Moseley, T. A., Haudenschild, D. R., Rose, L. & Reddi, A. H. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev.14, 155–174 (2003). ArticleCASPubMed 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). This paper, together with references 59 and 66, describes the existence of human TH17 cells and their possible regulation by cytokines. ArticleCAS Google Scholar
Bettelli, E., Oukka, M. & Kuchroo, V. K. TH-17 cells in the circle of immunity and autoimmunity. Nature Immunol.8, 345–350 (2007). ArticleCAS Google Scholar
Steinman, L. A brief history of TH17, the first major revision in the TH1/TH2 hypothesis of T cell-mediated tissue damage. Nature Med.13, 139–145 (2007). ArticleCASPubMed Google Scholar
Wei, L., Laurence, A., Elias, K. M. & O'Shea, J. J. IL-21 is produced by TH17 cells and drives IL-17 production in a STAT3-dependent manner. J. Biol. Chem.282, 34605–34610 (2007). ArticleCASPubMed Google Scholar
Yao, Z. et al. Herpesvirus saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity3, 811–821 (1995). ArticleCASPubMed Google Scholar
Toy, D. et al. Cutting edge: Interleukin-17 signals through a heteromeric receptor complex. J. Immunol.177, 36–39 (2006). ArticleCASPubMed Google Scholar
Shalom-Barak, T., Quach, J. & Lotz, M. Interleukin-17-induced gene expression in articular chondrocytes is associated with activation of mitogen-activated protein kinases and NF-κB. J. Biol. Chem.273, 27467–27473 (1998). ArticleCASPubMed Google Scholar
Schwandner, R., Yamaguchi, K. & Cao, Z. Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin-17 signal transduction. J. Exp. Med.191, 1233–1240 (2000). ArticleCASPubMedPubMed Central 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). ArticleCASPubMed 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). ArticleCAS Google Scholar
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). ArticleCASPubMed Google Scholar
Ruddy, M. J. et al. Functional cooperation between interleukin-17 and tumor necrosis factor-α is mediated by CCAAT/enhancer-binding protein family members. J. Biol. Chem.279, 2559–2567 (2004). ArticleCASPubMed Google Scholar
Ye, P. et al. Requirement of interleukin-17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J. Exp. Med.194, 519–527 (2001). ArticleCASPubMedPubMed Central Google Scholar
Nakae, S., Nambu, A., Sudo, K. & Iwakura, Y. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J. Immunol.171, 6173–6177 (2003). ArticleCASPubMed Google Scholar
Bush, K. A., Farmer, K. M., Walker, J. S. & Kirkham, B. W. Reduction of joint inflammation and bone erosion in rat adjuvant arthritis by treatment with interleukin-17 receptor IgG1 Fc fusion protein. Arthritis Rheum.46, 802–805 (2002). ArticleCASPubMed Google Scholar
Komiyama, Y. et al. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol.177, 566–573 (2006). ArticleCASPubMed Google Scholar
Hsu, H.-C. et al. Interleukin-17-producing T helper cells and interleukin-17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nature Immunol.9, 166–175 (2008). ArticleCAS Google Scholar
Nakae, S. et al. Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity17, 375–387 (2002). ArticleCASPubMed Google Scholar
Schnyder-Candrian, S. et al. Interleukin-17 is a negative regulator of established allergic asthma. J. Exp. Med.203, 2715–2725 (2006). ArticleCASPubMedPubMed Central Google Scholar
Happel, K. I. et al. Cutting edge: Roles of Toll-like receptor 4 and IL-23 in IL-17 expression in response to Klebsiella pneumoniae infection. J. Immunol.170, 4432–4436 (2003). ArticleCASPubMed Google Scholar
Shin, H. C. K., Benbernou, N., Esnault, S. & Guenounou, M. Expression of IL-17 in human memory CD45RO+ T lymphocytes and its regulation by protein kinase A pathway. Cytokine11, 257–266 (1999). ArticleCASPubMed Google Scholar
Michel, M. L. et al. Identification of an IL-17-producing NK1.1− iNKT cell population involved in airway neutrophilia. J. Exp. Med.204, 995–1001 (2007). ArticleCASPubMedPubMed Central Google Scholar
Khader, S. A. et al. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nature Immunol.8, 369–377 (2007). ArticleCAS Google Scholar
Shibata, K., Yamada, H., Hara, H., Kishihara, K. & Yoshikai, Y. Resident Vδ1+ γδ T cells control early infiltration of neutrophils after Escherichia coli infection via IL-17 production. J. Immunol.178, 4466–4472 (2007). ArticleCASPubMed 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. Immunity24, 179–189 (2006). This paper, together with references 68 and 69, shows that TH17-cell differentiation in mice is initiated by TGFβ and IL-6. Google Scholar
Hizawa, N., Kawaguchi, M., Huang, S. K. & Nishimura, M. Role of interleukin-17F in chronic inflammatory and allergic lung disease. Clin. Exp. Allergy36, 1109–1114 (2006). ArticleCASPubMed Google Scholar
Chang, S. H. & Dong, C. A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses. Cell Res.17, 435–440 (2007). ArticlePubMedCAS Google Scholar
Wright, J. F. et al. Identification of an interleukin-17F/17A heterodimer in activated human CD4+ T cells. J. Biol. Chem.282, 13447–13455 (2007). ArticleCASPubMed Google Scholar
Hurst, S. D. et al. New IL-17 family members promote TH1 or TH2 responses in the lung: in vivo function of the novel cytokine IL-25. J. Immunol.169, 443–453 (2002). ArticleCASPubMed Google Scholar
Oda, N. et al. Interleukin-17F induces pulmonary neutrophilia and amplifies antigen-induced allergic response. Am. J. Respir. Crit. Care Med.171, 12–18 (2005). ArticlePubMed Google Scholar
Kawaguchi, M. et al. Identification of a novel cytokine, ML-1, and its expression in subjects with asthma. J. Immunol.167, 4430–4435 (2001). ArticleCASPubMed Google Scholar
Hymowitz, S. G. et al. IL-17s adopt a cystine knot fold: structure and activity of a novel cytokine, IL-17F, and implications for receptor binding. Embo J.20, 5332–5341 (2001). ArticleCASPubMedPubMed Central Google Scholar
Kuestner, R. E. et al. Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F. J. Immunol.179, 5462–5473 (2007). ArticleCASPubMed Google Scholar
Chung, Y. et al. Expression and regulation of IL-22 in the IL-17-producing CD4+ T lymphocytes. Cell Res.16, 902–907 (2006). ArticleCASPubMed Google Scholar
Liang, S. C. et al. Interleukin (IL)-22 and IL-17 are coexpressed by TH17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med.203, 2271–2279 (2006). ArticleCASPubMedPubMed Central Google Scholar
Zheng, Y. et al. Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature445, 648–651 (2007). ArticleCASPubMed Google Scholar
Aujla, S. J. et al. IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nature Med.14, 275–281 (2008). ArticleCASPubMed Google Scholar
Zheng, Y. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nature Med.14, 282–289 (2008). ArticleCASPubMed Google Scholar
Kreymborg, K. et al. IL-22 is expressed by TH17 cells in an IL-23-dependent fashion, but not required for the development of autoimmune encephalomyelitis. J. Immunol.179, 8098–8104 (2007). ArticleCASPubMed Google Scholar
Zenewicz, L. A. et al. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity27, 647–659 (2007). ArticleCASPubMedPubMed Central 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). ArticleCAS Google Scholar
Nurieva, R. et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature448, 480–483 (2007). CASPubMed Google Scholar
Zhou, L. et al. IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nature Immunol.8, 967–974 (2007). References 60–62 describe the function of IL-21 in TH17-cell differentiation. ArticleCAS Google Scholar
Chtanova, T. et al. T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-TH1/TH2 effector cells that provide help for B cells. J. Immunol.173, 68–78 (2004). ArticleCASPubMed Google Scholar
Williams, I. R. CCR6 and CCL20: partners in intestinal immunity and lymphorganogenesis. Ann. NY Acad. Sci.1072, 52–61 (2006). ArticleCASPubMed Google Scholar
Hirota, K. et al. Preferential recruitment of CCR6-expressing TH17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J. Exp. Med.204, 2803–2812 (2007). ArticleCASPubMedPubMed Central Google Scholar
Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature441, 235–238 (2006). ArticleCASPubMed Google Scholar
Mangan, P. R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature441, 231–234 (2006). ArticleCASPubMed Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
Elias, K. M. et al. Retinoic acid inhibits TH17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood111, 1013–1020 (2008). ArticleCASPubMedPubMed Central Google Scholar
Kang, S. G., Lim, H. W., Andrisani, O. M., Broxmeyer, H. E. & Kim, C. H. Vitamin A metabolites induce gut-homing FoxP3+ regulatory T cells. J. Immunol.179, 3724–3733 (2007). ArticleCASPubMed Google Scholar
Mucida, D. et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science317, 256–260 (2007). ArticleCASPubMed Google Scholar
Schambach, F., Schupp, M., Lazar, M. A. & Reiner, S. L. Activation of retinoic acid receptor-α favours regulatory T cell induction at the expense of IL-17-secreting T helper cell differentiation. Eur. J. Immunol.37, 2396–2399 (2007). ArticleCASPubMed Google Scholar
Sun, C.-M. et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 TReg cells via retinoic acid. J. Exp. Med.204, 1775–1785 (2007). References 70–75 describe the function of retinoic acid in the promotion of FOXP3 expression, and references 71, 73 and 74 show that retinoic acid also inhibits TH17-cell differentiation. ArticleCASPubMedPubMed Central Google Scholar
Yang, X. O. et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J. Biol. Chem.282, 9358–9363 (2007). This paper, together with reference 95, describes the essential role of STAT3 in TH17-cell differentiation. ArticleCASPubMed Google Scholar
Ivanov, I. I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell126, 1121–1133 (2006). This paper identifies RORγt as a master transcription factor for TH17 cells. ArticleCASPubMed 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. Immunity26, 579–591 (2007). ArticleCASPubMed Google Scholar
Akimzhanov, A. M., Yang, X. O. & Dong, C. Chromatin remodeling of interleukin-17 (IL-17)–IL-17F cytokine gene locus during inflammatory helper T cell differentiation. J. Biol. Chem.282, 5969–5972 (2007). ArticleCASPubMed 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). ArticleCAS Google Scholar
Harada, M. et al. IL-21-induced Bɛ cell apoptosis mediated by natural killer T cells suppresses IgE responses. J. Exp. Med.203, 2929–2937 (2006). ArticleCASPubMedPubMed Central Google Scholar
Hunter, C. A. New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nature Rev. Immunol.5, 521–531 (2005). ArticleCAS Google Scholar
Cua, D. J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature421, 744–748 (2003). ArticleCASPubMed Google Scholar
Aggarwal, S., Ghilardi, N., Xie, M. H., De Sauvage, F. J. & Gurney, A. L. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J. Biol. Chem.278, 1910–1914 (2003). ArticleCASPubMed Google Scholar
Berenson, L. S., Yang, J., Sleckman, B. P., Murphy, T. L. & Murphy, K. M. Selective requirement of p38α MAPK in cytokine-dependent, but not antigen receptor-dependent, TH1 responses. J. Immunol.176, 4616–4621 (2006). ArticleCASPubMed Google Scholar
Thakker, P. et al. IL-23 is critical in the induction but not in the effector phase of experimental autoimmune encephalomyelitis. J. Immunol.178, 2589–2598 (2007). ArticleCASPubMed 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 TH17 cell-mediated pathology. Nature Immunol.8, 1390–1397 (2007). ArticleCAS Google Scholar
Duerr, R. H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science314, 1461–1463 (2006). ArticleCASPubMedPubMed Central Google Scholar
Wellcome Trust Case Control Consortium. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nature Genet.39, 1329–1337 (2007).
Uhlig, H. H. et al. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity25, 309–318 (2006). ArticleCASPubMed Google Scholar
Okamoto, H. & Momohara, S. Interleukin-12/23 monoclonal antibody for psoriasis. N. Engl. J. Med.356, 2003 (2007). CASPubMed Google Scholar
Langowski, J. L. et al. IL-23 promotes tumour incidence and growth. Nature442, 461–465 (2006). ArticleCASPubMed Google Scholar
Schiffenbauer, J. et al. The induction of EAE is only partially dependent on TNF receptor signaling but requires the IL-1 type I receptor. Clin. Immunol.95, 117–123 (2000). ArticleCASPubMed 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). ArticleCASPubMedPubMed Central Google Scholar
Laurence, A. et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity26, 371–381 (2007). ArticleCASPubMed Google Scholar
Batten, M. et al. Interleukin-27 limits autoimmune encephalomyelitis by suppressing the development of interleukin-17-producing T cells. Nature Immunol.7, 929–936 (2006). ArticleCAS Google Scholar
Stumhofer, J. S. et al. Interleukin-27 negatively regulates the development of interleukin-17-producing T helper cells during chronic inflammation of the central nervous system. Nature Immunol.7, 937–945 (2006). ArticleCAS Google Scholar
Afkarian, M. et al. T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. Nature Immunol.3, 549–557 (2002). ArticleCAS Google Scholar
Kurata, H., Lee, H. J., O'Garra, A. & Arai, N. Ectopic expression of activated Stat6 induces the expression of TH2-specific cytokines and transcription factors in developing TH1 cells. Immunity11, 677–688 (1999). ArticleCASPubMed Google Scholar
Mathur, A. N. et al. Stat3 and Stat4 direct development of IL-17-secreting TH cells. J. Immunol.178, 4901–4907 (2007). ArticleCASPubMed Google Scholar
Chen, Z. et al. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc. Natl Acad. Sci. USA103, 8137–8142 (2006). ArticleCASPubMedPubMed Central Google Scholar
Nishihara, M. et al. IL-6–gp130–STAT3 in T cells directs the development of IL-17+ TH with a minimum effect on that of TReg in the steady state. Int. Immunol.19, 695–702 (2007). ArticleCASPubMed Google Scholar
Kimura, A., Naka, T. & Kishimoto, T. IL-6-dependent and -independent pathways in the development of interleukin-17-producing T helper cells. Proc. Natl Acad. Sci. USA104, 12099–12104 (2007). ArticleCASPubMedPubMed Central Google Scholar
Yang, X. O. et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ. Immunity28, 29–39 (2008). This paper identifies RORα expression in TH17 cells and shows that RORα and RORγt together regulate TH17-cell development. ArticleCASPubMed Google Scholar
Harris, T. J. et al. Cutting edge: An in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity. J. Immunol.179, 4313–4317 (2007). ArticleCASPubMed Google Scholar
Jetten, A. M. Recent advances in the mechanisms of action and physiological functions of the retinoid-related orphan receptors (RORs). Curr. Drug Targets Inflamm. Allergy3, 395–412 (2004). ArticleCASPubMed Google Scholar
Eberl, G. & Littman, D. R. The role of the nuclear hormone receptor RORγt in the development of lymph nodes and Peyer's patches. Immunol. Rev.195, 81–90 (2003). ArticleCASPubMed Google Scholar
Brustle, A. et al. The development of inflammatory TH-17 cells requires interferon-regulatory factor 4. Nature Immunol.8, 958–966 (2007). ArticleCAS Google Scholar
Hu, C.-M., Jang, S. Y., Fanzo, J. C. & Pernis, A. B. Modulation of T cell cytokine production by interferon regulatory factor-4. J. Biol. Chem.277, 49238–49246 (2002). ArticleCASPubMed Google Scholar
Lohoff, M. et al. Dysregulated T helper cell differentiation in the absence of interferon regulatory factor 4. Proc. Natl Acad. Sci. USA99, 11808–11812 (2002). ArticleCASPubMedPubMed Central Google Scholar
Rengarajan, J. et al. Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression. J. Exp. Med.195, 1003–1012 (2002). ArticleCASPubMedPubMed Central Google Scholar
Lee, G. R., Kim, S. T., Spilianakis, C. G., Fields, P. E. & Flavell, R. A. T helper cell differentiation: regulation by cis elements and epigenetics. Immunity24, 369–379 (2006). ArticleCASPubMed Google Scholar
Moisan, J., Grenningloh, R., Bettelli, E., Oukka, M. & Ho, I. C. Ets-1 is a negative regulator of TH17 differentiation. J. Exp. Med.204, 2825–2835 (2007). ArticleCASPubMedPubMed Central Google Scholar
Young, D. A. et al. Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis. Arthritis Rheum.56, 1152–1163 (2007). ArticleCASPubMed Google Scholar
Spolski, R. & Leonard, W. J. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu. Rev. Immunol.26, 57–79 (2008). ArticleCASPubMed Google Scholar
Herber, D. et al. IL-21 has a pathogenic role in a lupus-prone mouse model and its blockade with IL-21R.Fc reduces disease progression. J. Immunol.178, 3822–3830 (2007). ArticleCASPubMed Google Scholar