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

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

Research output: Contribution to journal › Article › peer-review

141 Scopus citations

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.

Original language	English (US)
Pages (from-to)	54-66
Number of pages	13
Journal	Immunity
Volume	32
Issue number	1
DOIs	https://doi.org/10.1016/j.immuni.2009.12.003
State	Published - Jan 29 2010
Externally published	Yes

Keywords

CELLIMMUNO
MOLIMMUNO

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

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10.1016/j.immuni.2009.12.003

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Gulen, M. F., Kang, Z., Bulek, K., Youzhong, W., Kim, T. W., Chen, Y., Altuntas, C. Z., Sass Bak-Jensen, K., McGeachy, M. J., Do, J. S., Xiao, H., Delgoffe, G. M., Min, B., Powell, J. D., Tuohy, V. K., Cua, D. J., & Li, X. (2010). The Receptor SIGIRR Suppresses Th17 Cell Proliferation via Inhibition of the Interleukin-1 Receptor Pathway and mTOR Kinase Activation. Immunity, 32(1), 54-66. https://doi.org/10.1016/j.immuni.2009.12.003

Gulen, MF, Kang, Z, Bulek, K, Youzhong, W, Kim, TW, Chen, Y, Altuntas, CZ, Sass Bak-Jensen, K, McGeachy, MJ, Do, JS, Xiao, H, Delgoffe, GM, Min, B, Powell, JD, Tuohy, VK, Cua, DJ & Li, X 2010, 'The Receptor SIGIRR Suppresses Th17 Cell Proliferation via Inhibition of the Interleukin-1 Receptor Pathway and mTOR Kinase Activation', Immunity, vol. 32, no. 1, pp. 54-66. https://doi.org/10.1016/j.immuni.2009.12.003

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

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 (MOG35-55) 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.",

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author = "Gulen, {Muhammet F.} and Zizhen Kang and Katarzyna Bulek and Wan Youzhong and Kim, {Tae Whan} and Yi Chen and Altuntas, {Cengiz Z.} and {Sass Bak-Jensen}, Kristian and McGeachy, {Mandy J.} and Do, {Jeong Su} and Hui Xiao and Delgoffe, {Greg M.} and Booki Min and Powell, {Jonathan D.} and Tuohy, {Vincent K.} and Cua, {Daniel J.} and Xiaoxia Li",

note = "Funding Information: This work was supported by grants from NIH (RO1 Al060632 to X.L.) and a grant from National Multiple Sclerosis Society (X.L.). The plasmid p5′ CD2/coding-CD2 and p3′ CD2 was provided by D. Kioussis of the National Institute for Medical Research, London, UK. Cre-GFP-RV was a generous gift from W. Paul at National Institutes of Health. We thank J. Thomas (UT Southwestern) for providing us with the IRAK1 −/− mice and W.-c. Yeh (Amgen) for providing us with the IRAK4 −/− mice. ",

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doi = "10.1016/j.immuni.2009.12.003",

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T1 - The Receptor SIGIRR Suppresses Th17 Cell Proliferation via Inhibition of the Interleukin-1 Receptor Pathway and mTOR Kinase Activation

AU - Gulen, Muhammet F.

AU - Kang, Zizhen

AU - Bulek, Katarzyna

AU - Youzhong, Wan

AU - Kim, Tae Whan

AU - Chen, Yi

AU - Altuntas, Cengiz Z.

AU - Sass Bak-Jensen, Kristian

AU - McGeachy, Mandy J.

AU - Do, Jeong Su

AU - Xiao, Hui

AU - Delgoffe, Greg M.

AU - Min, Booki

AU - Powell, Jonathan D.

AU - Tuohy, Vincent K.

AU - Cua, Daniel J.

AU - Li, Xiaoxia

N1 - Funding Information: This work was supported by grants from NIH (RO1 Al060632 to X.L.) and a grant from National Multiple Sclerosis Society (X.L.). The plasmid p5′ CD2/coding-CD2 and p3′ CD2 was provided by D. Kioussis of the National Institute for Medical Research, London, UK. Cre-GFP-RV was a generous gift from W. Paul at National Institutes of Health. We thank J. Thomas (UT Southwestern) for providing us with the IRAK1 −/− mice and W.-c. Yeh (Amgen) for providing us with the IRAK4 −/− mice.

PY - 2010/1/29

Y1 - 2010/1/29

N2 - 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 (MOG35-55) 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.

AB - 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 (MOG35-55) 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.

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KW - MOLIMMUNO

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AN - SCOPUS:74649086985

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JF - Immunity

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

Abstract

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