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

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

Research output: Contribution to journalArticle

13 Citations (Scopus)

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-A nd 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.

Original languageEnglish (US)
Article number1485
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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Immunoglobulin Variable Region
Interleukin-23
Interleukin-17
T-Lymphocytes
Th17 Cells
imiquimod
Dendritic Cells
Protein Domains
Peripheral Tolerance
CD4 Antigens
Antigen-Presenting Cells
Psoriasis
Innate Immunity
Immunoglobulin Domains

ASJC Scopus subject areas

  • General

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Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis. / Li, Na; Xu, Wenwen; Yuan, Ying; Ayithan, Natarajan; Imai, Yasutomo; Wu, Xuesong; Miller, Halli; Olson, Michael; Feng, Yunfeng; Huang, Yina H.; Jo Turk, Mary; Hwang, Samuel T; Malarkannan, Subramaniam; Wang, Li.

In: Scientific Reports, Vol. 7, No. 1, 1485, 01.12.2017.

Research output: Contribution to journalArticle

Li, N, Xu, W, Yuan, Y, Ayithan, N, Imai, Y, Wu, X, Miller, H, Olson, M, Feng, Y, Huang, YH, Jo Turk, M, Hwang, ST, Malarkannan, S & Wang, L 2017, 'Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis', Scientific Reports, vol. 7, no. 1, 1485. https://doi.org/10.1038/s41598-017-01411-1
Li, Na ; Xu, Wenwen ; Yuan, Ying ; Ayithan, Natarajan ; Imai, Yasutomo ; Wu, Xuesong ; Miller, Halli ; Olson, Michael ; Feng, Yunfeng ; Huang, Yina H. ; Jo Turk, Mary ; Hwang, Samuel T ; Malarkannan, Subramaniam ; Wang, Li. / Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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AU - Olson, Michael

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AB - 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-A nd 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.

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