Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses. Proc Natl Acad Sci U S A 2015 May 26;112(21):6682-7
Date
05/13/2015Pubmed ID
25964334Pubmed Central ID
PMC4450438DOI
10.1073/pnas.1420370112Scopus ID
2-s2.0-84930208138 (requires institutional sign-in at Scopus site) 317 CitationsAbstract
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.
Author List
Liu J, Yuan Y, Chen W, Putra J, Suriawinata AA, Schenk AD, Miller HE, Guleria I, Barth RJ, Huang YH, Wang LMESH terms used to index this publication - Major topics in bold
AnimalsAntibodies, Monoclonal
Antigens
B7-H1 Antigen
Female
Immune Tolerance
Ligands
Lymphocyte Activation
Male
Membrane Proteins
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Neoplasms, Experimental
Programmed Cell Death 1 Receptor
T-Lymphocytes
