Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis
Na Li, [Li, Na; Xu, Wenwen; Yuan, Ying; Ayithan, Natarajan; Miller, Halli; Olson, Michael; Malarkannan, Subramaniam; Wang, Li] Dept Microbiol & Immunol, Milwaukee, WI 53226 USA; [Imai, Yasutomo; Wu, Xuesong; Hwang, Samuel T.] Med Coll Wisconsin, Dept Dermatol, Milwaukee, WI 53226 USA; [Malarkannan, Subramaniam] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA; [Malarkannan, Subramaniam] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA; [Malarkannan, Subramaniam] Dept Blood Res Inst, Milwaukee, WI 53226 USA; [Wu, Xuesong; Feng, Yunfeng; Huang, Yina H.; Turk, Mary Jo] Geisel Sch Med Dartmouth, Dept Microbiol & Immunol, Hanover, NH USA; [Yuan, Ying] Shanghai Univ Tradit Chinese Med, Coll Pharm, Shanghai 201203, Peoples R China; [Ayithan, Natarajan] Univ Maryland, Inst Human Virol, Sch Med, Baltimore, MD 21201 USA; [Imai, Yasutomo] Hyogo Coll Med, Dept Dermatol, 1-1 Mukogawa Cho, Nishinomiya, Hyogo 6638501, Japan; [Hwang, Samuel T.] Univ Calif Davis, Dept Dermatol, Sacramento, CA 95816 USA; [Li, Na] Harbin Med Univ, Dept Histol & Embryol, Harbin 150086, Peoples R China
Wenwen Xu, [Li, Na; Xu, Wenwen; Yuan, Ying; Ayithan, Natarajan; Miller, Halli; Olson, Michael; Malarkannan, Subramaniam; Wang, Li] Dept Microbiol & Immunol, Milwaukee, WI 53226 USA; [Imai, Yasutomo; Wu, Xuesong; Hwang, Samuel T.] Med Coll Wisconsin, Dept Dermatol, Milwaukee, WI 53226 USA; [Malarkannan, Subramaniam] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA; [Malarkannan, Subramaniam] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA; [Malarkannan, Subramaniam] Dept Blood Res Inst, Milwaukee, WI 53226 USA; [Wu, Xuesong; Feng, Yunfeng; Huang, Yina H.; Turk, Mary Jo] Geisel Sch Med Dartmouth, Dept Microbiol & Immunol, Hanover, NH USA; [Yuan, Ying] Shanghai Univ Tradit Chinese Med, Coll Pharm, Shanghai 201203, Peoples R China; [Ayithan, Natarajan] Univ Maryland, Inst Human Virol, Sch Med, Baltimore, MD 21201 USA; [Imai, Yasutomo] Hyogo Coll Med, Dept Dermatol, 1-1 Mukogawa Cho, Nishinomiya, Hyogo 6638501, Japan; [Hwang, Samuel T.] Univ Calif Davis, Dept Dermatol, Sacramento, CA 95816 USA; [Li, Na] Harbin Med Univ, Dept Histol & Embryol, Harbin 150086, Peoples R China
Ying Yuan, [Li, Na; Xu, Wenwen; Yuan, Ying; Ayithan, Natarajan; Miller, Halli; Olson, Michael; Malarkannan, Subramaniam; Wang, Li] Dept Microbiol & Immunol, Milwaukee, WI 53226 USA; [Imai, Yasutomo; Wu, Xuesong; Hwang, Samuel T.] Med Coll Wisconsin, Dept Dermatol, Milwaukee, WI 53226 USA; [Malarkannan, Subramaniam] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA; [Malarkannan, Subramaniam] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA; [Malarkannan, Subramaniam] Dept Blood Res Inst, Milwaukee, WI 53226 USA; [Wu, Xuesong; Feng, Yunfeng; Huang, Yina H.; Turk, Mary Jo] Geisel Sch Med Dartmouth, Dept Microbiol & Immunol, Hanover, NH USA; [Yuan, Ying] Shanghai Univ Tradit Chinese Med, Coll Pharm, Shanghai 201203, Peoples R China; [Ayithan, Natarajan] Univ Maryland, Inst Human Virol, Sch Med, Baltimore, MD 21201 USA; [Imai, Yasutomo] Hyogo Coll Med, Dept Dermatol, 1-1 Mukogawa Cho, Nishinomiya, Hyogo 6638501, Japan; [Hwang, Samuel T.] Univ Calif Davis, Dept Dermatol, Sacramento, CA 95816 USA; [Li, Na] Harbin Med Univ, Dept Histol & Embryol, Harbin 150086, Peoples R China
Natarajan Ayithan, [Li, Na; Xu, Wenwen; Yuan, Ying; Ayithan, Natarajan; Miller, Halli; Olson, Michael; Malarkannan, Subramaniam; Wang, Li] Dept Microbiol & Immunol, Milwaukee, WI 53226 USA; [Imai, Yasutomo; Wu, Xuesong; Hwang, Samuel T.] Med Coll Wisconsin, Dept Dermatol, Milwaukee, WI 53226 USA; [Malarkannan, Subramaniam] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA; [Malarkannan, Subramaniam] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA; [Malarkannan, Subramaniam] Dept Blood Res Inst, Milwaukee, WI 53226 USA; [Wu, Xuesong; Feng, Yunfeng; Huang, Yina H.; Turk, Mary Jo] Geisel Sch Med Dartmouth, Dept Microbiol & Immunol, Hanover, NH USA; [Yuan, Ying] Shanghai Univ Tradit Chinese Med, Coll Pharm, Shanghai 201203, Peoples R China; [Ayithan, Natarajan] Univ Maryland, Inst Human Virol, Sch Med, Baltimore, MD 21201 USA; [Imai, Yasutomo] Hyogo Coll Med, Dept Dermatol, 1-1 Mukogawa Cho, Nishinomiya, Hyogo 6638501, Japan; [Hwang, Samuel T.] Univ Calif Davis, Dept Dermatol, Sacramento, CA 95816 USA; [Li, Na] Harbin Med Univ, Dept Histol & Embryol, Harbin 150086, Peoples R China
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 TCR gamma delta T+ cells and CD4(+) Th17 cells. Furthermore, VISTA regulates the peripheral homeostasis of CD27(-) gamma delta T cells and their activation upon TCR-mediated or cytokine-mediated stimulation. IL-17A-producing CD27(-) gamma delta 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 TCR gamma delta(+) 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.
