Journal
SCIENTIFIC REPORTS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-017-01411-1
Keywords
-
Categories
Funding
- Advancing A Healthier Wisconsin Research and Education Program (AHW REP) fund
- Ann's Hope Foundation from the Medical College of Wisconsin Cancer Center
- Office of the Assistant Secretary of Defense for Health Affairs [W81XWH-14-1-0587]
- Worldwide Cancer Research Foundation (UK) [16-1161]
- Uehara Foundation
- Nicholas Family Foundation
- Gardetto Family
- [NCI R01 CA164225]
- [NIH R01 AI102893]
- [NCI R01 CA179363]
- [NIH R01 AI089805]
- [NIH R01AR063091 NIAMS]
- [NIH R01 CA120777]
- Grants-in-Aid for Scientific Research [15K09796] Funding Source: KAKEN
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available