Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses.

Abstract

V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a negative immune-checkpoint protein that suppresses T-cell responses. To determine whether VISTA synergizes with another immune-checkpoint, programmed death 1 (PD-1), this study characterizes the immune responses in VISTA-deficient, PD-1-deficient (KO) mice and VISTA/PD-1 double KO mice. Chronic inflammation and spontaneous activation of T cells were observed in both single KO mice, demonstrating their nonredundancy. However, the VISTA/PD-1 double KO mice exhibited significantly higher levels of these phenotypes than the single KO mice. When bred onto the 2D2 T-cell receptor transgenic mice, which are predisposed to development of inflammatory autoimmune disease in the CNS, the level of disease penetrance was significantly enhanced in the double KO mice compared with in the single KO mice. Consistently, the magnitude of T-cell response toward foreign antigens was synergistically higher in the VISTA/PD-1 double KO mice. A combinatorial blockade using monoclonal antibodies specific for VISTA and PD-L1 achieved optimal tumor-clearing therapeutic efficacy. In conclusion, our study demonstrates the nonredundant role of VISTA that is distinct from the PD-1/PD-L1 pathway in controlling T-cell activation. These findings provide the rationale to concurrently target VISTA and PD-1 pathways for treating T-cell-regulated diseases such as cancer.

• Authors: Jun Liu, Ying Yuan, Wenna Chen, Juan Putra, Arief A Suriawinata, Austin D Schenk, Halli E Miller, Indira Guleria, Richard J Barth, Yina H Huang, Li Wang
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 21 Pg. 6682-7 (May 26 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 25964334 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Antigens
• B7-H1 Antigen
• Cd274 protein, mouse
• Ligands
• Membrane Proteins
• Pdcd1 protein, mouse
• Programmed Cell Death 1 Receptor
• Vsir protein, mouse

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage)
• Antigens (administration & dosage)
• B7-H1 Antigen (deficiency, genetics, metabolism)
• Female
• Immune Tolerance
• Ligands
• Lymphocyte Activation
• Male
• Membrane Proteins (deficiency, genetics, immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Neoplasms, Experimental (immunology)
• Programmed Cell Death 1 Receptor (deficiency, genetics, immunology)
• T-Lymphocytes (immunology)