Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17–producing T cells

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).

Hibbert, L., Pflanz, S., De Waal Malefyt, 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).

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).

Takeda, A. et al. Cutting edge: role of IL-27/WSX-1 signaling for induction of T-bet through activation of STAT1 during initial Th1 commitment. J. Immunol. 170, 4886–4890 (2003).

Chen, Q. et al. Development of Th1-type immune responses requires the type I cytokine receptor TCCR. Nature 407, 916–920 (2000).

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

Sprecher, C.A. et al. Cloning and characterization of a novel class I cytokine receptor. Biochem. Biophys. Res. Commun. 246, 82–90 (1998).

Holscher, C. et al. The IL-27 receptor chain WSX-1 differentially regulates antibacterial immunity and survival during experimental tuberculosis. J. Immunol. 174, 3534–3544 (2005).

Pearl, J.E. et al. IL-27 signaling compromises control of bacterial growth in mycobacteria-infected mice. J. Immunol. 173, 7490–7496 (2004).

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

Yoshida, H. et al. WSX-1 is required for the initiation of Th1 responses and resistance to L. major infection. Immunity 15, 569–578 (2001).

Artis, D. et al. The IL-27 receptor (WSX-1) is an inhibitor of innate and adaptive elements of type 2 immunity. J. Immunol. 173, 5626–5634 (2004).

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

Miyazaki, Y. et al. Exacerbation of experimental allergic asthma by augmented Th2 responses in WSX-1-deficient mice. J. Immunol. 175, 2401–2407 (2005).

Yamanaka, A. et al. Hyperproduction of proinflammatory cytokines by WSX-1-deficient NKT cells in concanavalin A-induced hepatitis. J. Immunol. 172, 3590–3596 (2004).

Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005).

McKenzie, B.S., Kastelein, R.A. & Cua, D.J. Understanding the IL-23-IL-17 immune pathway. Trends Immunol. 27, 17–23 (2006).

Langrish, C.L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).

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. Nat. Immunol. 6, 1123–1132 (2005).

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).

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).

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).

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).

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).

Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

Mangan, P.R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).

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

Owaki, T. et al. IL-27 suppresses CD28-mediated IL-2 production through suppressor of cytokine signaling 3. J. Immunol. 176, 2773–2780 (2006).

Bettelli, E. et al. Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. J. Exp. Med. 200, 79–87 (2004).

Pasare, C. & Medzhitov, R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299, 1033–1036 (2003).

Kolls, J.K. & Linden, A. Interleukin-17 family members and inflammation. Immunity 21, 467–476 (2004).

Sergejeva, S., Ivanov, S., Lotvall, J. & Linden, A. Interleukin-17 as a recruitment and survival factor for airway macrophages in allergic airway inflammation. Am. J. Respir. Cell Mol. Biol. 33, 248–253 (2005).

McQualter, J.L. et al. Granulocyte macrophage colony-stimulating factor: a new putative therapeutic target in multiple sclerosis. J. Exp. Med. 194, 873–882 (2001).

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).

Cho, M.L. et al. STAT3 and NF-κB signal pathway is required for IL-23-mediated IL-17 production in spontaneous arthritis animal model IL-1 receptor antagonist-deficient mice. J. Immunol. 176, 5652–5661 (2006).

Chen, Z. et al. Selective regulatory function of SOCS3 in the formation of IL-17-secreting T cells. Proc. Natl. Acad. Sci. USA 103, 8137–8142 (2006).

Schimpl, A. et al. IL-2 and autoimmune disease. Cytokine Growth Factor Rev. 13, 369–378 (2002).

Honda, K. et al. T helper 1-inducing property of IL-27/WSX-1 signaling is required for the induction of experimental colitis. Inflamm. Bowel Dis. 11, 1044–1052 (2005).

Jebbari, H., Roberts, C.W., Ferguson, D.J., Bluethmann, H. & Alexander, J. A protective role for IL-6 during early infection with Toxoplasma gondii. Parasite Immunol. 20, 231–239 (1998).

Suzuki, Y. et al. Impaired resistance to the development of toxoplasmic encephalitis in interleukin-6-deficient mice. Infect. Immun. 65, 2339–2345 (1997).

Gao, W. & Pereira, M.A. Interleukin-6 is required for parasite specific response and host resistance to Trypanosoma cruzi. Int. J. Parasitol. 32, 167–170 (2002).

Kelly, M.N. et al. Interleukin-17/interleukin-17 receptor-mediated signaling is important for generation of an optimal polymorphonuclear response against Toxoplasma gondii infection. Infect. Immun. 73, 617–621 (2005).

Doganci, A., Sauer, K., Karwot, R. & Finotto, S. Pathological role of IL-6 in the experimental allergic bronchial asthma in mice. Clin. Rev. Allergy Immunol. 28, 257–270 (2005).

Sedgwick, J.D. et al. Isolation and direct characterization of resident microglial cells from the normal and inflamed central nervous system. Proc. Natl. Acad. Sci. USA 88, 7438–7442 (1991).