title: 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.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226; Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, People's Republic of China;
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226;
authors.forename: Ying
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226;
authors.forename: Wenna
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Pathology and.
authors.forename: Juan
authors.initials: J
authors.lastname: Putra
authors.affiliation: Department of Pathology and.
authors.forename: Arief A
authors.initials: AA
authors.lastname: Suriawinata
authors.affiliation: Department of Surgery, Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center, Lebanon, NH 03756; and.
authors.forename: Austin D
authors.initials: AD
authors.lastname: Schenk
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226;
authors.forename: Halli E
authors.initials: HE
authors.lastname: Miller
authors.affiliation: Boston Children's Hospital and Brigham and Women's Hospital, Renal Division, Harvard Medical School, Boston, MA 02115.
authors.forename: Indira
authors.initials: I
authors.lastname: Guleria
authors.affiliation: Department of Surgery, Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center, Lebanon, NH 03756; and.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Barth
authors.affiliation: Department of Pathology and.
authors.forename: Yina H
authors.initials: YH
authors.lastname: Huang
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226; lilywang@mcw.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000941:Antigens / Q000008:administration & dosage; D060890:B7-H1 Antigen / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005260:Female; D007108:Immune Tolerance; D008024:Ligands; D008213:Lymphocyte Activation; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008024:Ligands; D008565:Membrane Proteins; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; C548983:Vsir protein, mouse
keywords: T-cell activation; autoimmunity; cancer immunotherapy; immune-checkpoint; tumor immunity