The receptor SIGIRR suppresses Th17 cell proliferation via inhibition of the interleukin-1 receptor pathway and mTOR kinase activation

Muhammet F Gulen; 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; Daniel J Cua; Xiaoxia Li

doi:10.1016/j.immuni.2009.12.003

The receptor SIGIRR suppresses Th17 cell proliferation via inhibition of the interleukin-1 receptor pathway and mTOR kinase activation

Immunity. 2010 Jan 29;32(1):54-66. doi: 10.1016/j.immuni.2009.12.003. Epub 2010 Jan 7.

Authors

Muhammet F Gulen¹, 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, Daniel J Cua, Xiaoxia Li

Affiliation

¹ Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / immunology*
Cell Lineage / immunology
Cell Proliferation
Cell Separation
Encephalomyelitis, Autoimmune, Experimental / immunology
Encephalomyelitis, Autoimmune, Experimental / pathology
Enzyme Activation / immunology
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Immunoblotting
Immunoprecipitation
Interleukin-17 / immunology*
Interleukin-17 / metabolism
Intracellular Signaling Peptides and Proteins / immunology*
Intracellular Signaling Peptides and Proteins / metabolism
Mice
Mice, Knockout
Protein Serine-Threonine Kinases / immunology*
Protein Serine-Threonine Kinases / metabolism
Receptors, Interleukin-1 / immunology*
Receptors, Interleukin-1 / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / immunology
T-Lymphocyte Subsets / cytology
T-Lymphocyte Subsets / immunology
T-Lymphocyte Subsets / metabolism
T-Lymphocytes, Helper-Inducer / cytology*
T-Lymphocytes, Helper-Inducer / immunology
T-Lymphocytes, Helper-Inducer / metabolism
TOR Serine-Threonine Kinases
Transfection

Substances

Interleukin-17
Intracellular Signaling Peptides and Proteins
Receptors, Interleukin-1
SIGIRR protein, mouse
mTOR protein, mouse
Protein Serine-Threonine Kinases
TOR Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding