The receptor SIGIRR suppresses Th17 cell proliferation via inhibition of the interleukin-1 receptor pathway and mTOR kinase activation.
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.
Gulen
Muhammet F
MF
Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Kang
Zizhen
Z
Bulek
Katarzyna
K
Youzhong
Wan
W
Kim
Tae Whan
TW
Chen
Yi
Y
Altuntas
Cengiz Z
CZ
Sass Bak-Jensen
Kristian
K
McGeachy
Mandy J
MJ
Do
Jeong-Su
JS
Xiao
Hui
H
Delgoffe
Greg M
GM
Min
Booki
B
Powell
Jonathan D
JD
Tuohy
Vincent K
VK
Cua
Daniel J
DJ
Li
Xiaoxia
X
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D019070:Cell Lineage / Q000276:immunology; D049109:Cell Proliferation; D002469:Cell Separation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology; D004789:Enzyme Activation / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015151:Immunoblotting; D047468:Immunoprecipitation; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000276:immunology* / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D014162:Transfection
D020381:Interleukin-17; D047908:Intracellular Signaling Peptides and Proteins; D017472:Receptors, Interleukin-1; C484529:SIGIRR protein, mouse; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases