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The Receptor SIGIRR Suppresses Th17 Cell Proliferation via Inhibition of the Interleukin-1 Receptor Pathway and mTOR Kinase Activation

2010; Cell Press; Volume: 32; Issue: 1 Linguagem: Inglês

10.1016/j.immuni.2009.12.003

1097-4180

Muhammet F. Gülen, Zizhen Kang, Katarzyna Bulek, Wan Youzhong, Tae Whan Kim, Yi Chen, Cengiz Z. Altuntas, Kristian Sass Bak‐Jensen, Mandy J. McGeachy, Jeong‐su Do, Hui Xiao, Greg M. Delgoffe, Booki Min, Jonathan D. Powell, Vincent K. Tuohy, J. Daniel, Xiaoxia Li,

Immunotherapy and Immune Responses

Summary Interleukin-1 (IL-1)-mediated signaling in T cells is essential for T helper 17 (Th17) cell differentiation. We showed here that SIGIRR, a negative regulator of IL-1 receptor and Toll-like receptor signaling, was induced during Th17 cell lineage commitment and governed Th17 cell differentiation and expansion through its inhibitory effects on IL-1 signaling. The absence of SIGIRR in T cells resulted in increased Th17 cell polarization in vivo upon myelin oligodendrocyte glycoprotein (MOG 35-55 ) peptide immunization. Recombinant IL-1 promoted a marked increase in the proliferation of SIGIRR-deficient T cells under an in vitro Th17 cell-polarization condition. Importantly, we detected increased IL-1-induced phosphorylation of JNK and mTOR kinase in SIGIRR-deficient Th17 cells compared to wild-type Th17 cells. IL-1-induced proliferation was abolished in mTOR-deficient Th17 cells, indicating the essential role of mTOR activation. Our results demonstrate an important mechanism by which SIGIRR controls Th17 cell expansion and effector function through the IL-1-induced mTOR signaling pathway.