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A limitation to antitumor immunity is the dysfunction of T cells in the tumor microenvironment, in part due to upregulation of coinhibitory receptors such as PD-1. Here, we describe that poliovirus receptor-related immunoglobulin domain protein (PVRIG) acts as a coinhibitory receptor in mice. Murine PVRIG interacted weakly with poliovirus receptor (PVR) but bound poliovirus receptor-like 2 (PVRL2) strongly, making the latter its principal ligand. As in humans, murine NK and NKT cells constitutively expressed PVRIG. However, when compared with humans, less PVRIG transcript and surface protein was detected in murine CD8 + T cells ex vivo However, activated CD8 + T cells upregulated PVRIG expression. In the mouse tumor microenvironment, infiltrating CD8 + T cells expressed PVRIG whereas its ligand, PVRL2, was detected predominantly on myeloid cells and tumor cells, mirroring the expression pattern in human tumors. PVRIG-deficient mouse CD8 + T cells mounted a stronger antigen-specific effector response compared with wild-type CD8 + T cells during acute Listeria monocytogenes infection. Furthermore, enhanced CD8 + T-cell effector function inhibited tumor growth in PVRIG -/- mice compared with wild-type mice and PD-L1 blockade conferred a synergistic antitumor response in PVRIG -/- mice. Therapeutic intervention with antagonistic anti-PVRIG in combination with anti-PD-L1 reduced tumor growth. Taken together, our results suggest PVRIG is an inducible checkpoint receptor and that targeting PVRIG-PVRL2 interactions results in increased CD8 + T-cell function and reduced tumor growth. See related article on p. 257 ., (©2019 American Association for Cancer Research.)