Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis

Abstract V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) is an inhibitory immune-checkpoint molecule that suppresses CD4+ and CD8+ T cell activation when expressed on antigen-presenting cells. Vsir −/− mice developed loss of peripheral tolerance and multi-organ chronic inflammatory p...

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Autores principales:	Na Li, Wenwen Xu, Ying Yuan, Natarajan Ayithan, Yasutomo Imai, Xuesong Wu, Halli Miller, Michael Olson, Yunfeng Feng, Yina H. Huang, Mary Jo Turk, Samuel T. Hwang, Subramaniam Malarkannan, Li Wang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1b0571cb47a145ed901429ee57439f62
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spelling	oai:doaj.org-article:1b0571cb47a145ed901429ee57439f622021-12-02T11:52:59ZImmune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis10.1038/s41598-017-01411-12045-2322https://doaj.org/article/1b0571cb47a145ed901429ee57439f622017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01411-1https://doaj.org/toc/2045-2322Abstract V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) is an inhibitory immune-checkpoint molecule that suppresses CD4+ and CD8+ T cell activation when expressed on antigen-presenting cells. Vsir −/− mice developed loss of peripheral tolerance and multi-organ chronic inflammatory phenotypes. Vsir −/− CD4+ and CD8+ T cells were hyper-responsive towards self- and foreign antigens. Whether or not VISTA regulates innate immunity is unknown. Using a murine model of psoriasis induced by TLR7 agonist imiquimod (IMQ), we show that VISTA deficiency exacerbated psoriasiform inflammation. Enhanced TLR7 signaling in Vsir −/− dendritic cells (DCs) led to the hyper-activation of Erk1/2 and Jnk1/2, and augmented the production of IL-23. IL-23, in turn, promoted the expression of IL-17A in both TCRγδ+ T cells and CD4+ Th17 cells. Furthermore, VISTA regulates the peripheral homeostasis of CD27− γδ T cells and their activation upon TCR-mediated or cytokine-mediated stimulation. IL-17A-producing CD27− γδ T cells were expanded in the Vsir −/− mice and amplified the inflammatory cascade. In conclusion, this study has demonstrated that VISTA critically regulates the inflammatory responses mediated by DCs and IL-17-producing TCRγδ+ and CD4+ Th17 T cells following TLR7 stimulation. Our finding provides a rationale for therapeutically enhancing VISTA-mediated pathways to benefit the treatment of autoimmune and inflammatory disorders.Na LiWenwen XuYing YuanNatarajan AyithanYasutomo ImaiXuesong WuHalli MillerMichael OlsonYunfeng FengYina H. HuangMary Jo TurkSamuel T. HwangSubramaniam MalarkannanLi WangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Na Li Wenwen Xu Ying Yuan Natarajan Ayithan Yasutomo Imai Xuesong Wu Halli Miller Michael Olson Yunfeng Feng Yina H. Huang Mary Jo Turk Samuel T. Hwang Subramaniam Malarkannan Li Wang Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis
description	Abstract V-domain Immunoglobulin Suppressor of T cell Activation (VISTA) is an inhibitory immune-checkpoint molecule that suppresses CD4+ and CD8+ T cell activation when expressed on antigen-presenting cells. Vsir −/− mice developed loss of peripheral tolerance and multi-organ chronic inflammatory phenotypes. Vsir −/− CD4+ and CD8+ T cells were hyper-responsive towards self- and foreign antigens. Whether or not VISTA regulates innate immunity is unknown. Using a murine model of psoriasis induced by TLR7 agonist imiquimod (IMQ), we show that VISTA deficiency exacerbated psoriasiform inflammation. Enhanced TLR7 signaling in Vsir −/− dendritic cells (DCs) led to the hyper-activation of Erk1/2 and Jnk1/2, and augmented the production of IL-23. IL-23, in turn, promoted the expression of IL-17A in both TCRγδ+ T cells and CD4+ Th17 cells. Furthermore, VISTA regulates the peripheral homeostasis of CD27− γδ T cells and their activation upon TCR-mediated or cytokine-mediated stimulation. IL-17A-producing CD27− γδ T cells were expanded in the Vsir −/− mice and amplified the inflammatory cascade. In conclusion, this study has demonstrated that VISTA critically regulates the inflammatory responses mediated by DCs and IL-17-producing TCRγδ+ and CD4+ Th17 T cells following TLR7 stimulation. Our finding provides a rationale for therapeutically enhancing VISTA-mediated pathways to benefit the treatment of autoimmune and inflammatory disorders.
format	article
author	Na Li Wenwen Xu Ying Yuan Natarajan Ayithan Yasutomo Imai Xuesong Wu Halli Miller Michael Olson Yunfeng Feng Yina H. Huang Mary Jo Turk Samuel T. Hwang Subramaniam Malarkannan Li Wang
author_facet	Na Li Wenwen Xu Ying Yuan Natarajan Ayithan Yasutomo Imai Xuesong Wu Halli Miller Michael Olson Yunfeng Feng Yina H. Huang Mary Jo Turk Samuel T. Hwang Subramaniam Malarkannan Li Wang
author_sort	Na Li
title	Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis
title_short	Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis
title_full	Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis
title_fullStr	Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis
title_full_unstemmed	Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis
title_sort	immune-checkpoint protein vista critically regulates the il-23/il-17 inflammatory axis
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/1b0571cb47a145ed901429ee57439f62
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_version_	1718394910382489600

Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis

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