Integrative Roles of NK Receptors and γδ TCRs in γδ T Cell-Mediated Cancer Immunity.

Abstract

γδ T cells employ dual recognition strategies that integrate innate and adaptive immune sensing through NK receptors (NKRs) and γδ-TCRs in cancer immunity. Through the coordinated use of clonotypic γδ-TCRs and germline-encoded NKRs, γδ T cells recognize malignant cells in an MHC-unrestricted manner and exert potent cytotoxic and immunomodulatory functions. In this review, we discuss how activating and inhibitory NKRs-including NKG-2D, natural cytotoxicity receptors, CD16, NKG-2A, and killer cell immunoglobulin-like receptors-are expressed across major human γδ T cell subsets and how their signals are integrated with γδ-TCRs. We highlight subset-specific differential utilization of NKRs in circulating Vδ2 and tissue-resident Vδ1 γδ T cells, context-dependent integration of γδ-TCR and NKR signaling within the tumor microenvironment, and emerging implications for γδ T cell-based cancer immunotherapy.