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

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26 Scopus citations

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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    Li, N., Xu, W., Yuan, Y., Ayithan, N., Imai, Y., Wu, X., Miller, H., Olson, M., Feng, Y., Huang, Y. H., Jo Turk, M., Hwang, S. T., Malarkannan, S., & Wang, L. (2017). Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis. Scientific Reports, 7(1), [1485]. https://doi.org/10.1038/s41598-017-01411-1