Killer-cell immunoglobulin-like receptors define a potent effector program in human γδ T cells.

Human γδ T cells are a rare but functionally diverse lymphocyte subset critical for tumor surveillance and antimicrobial immunity. Although they express NK cell-associated receptors such as killer-cell immunoglobulin-like receptors (KIRs), the relevance of KIR expression on γδ T cells remains largely unexplored. Using flow cytometry, ATAC-seq, and RNA-seq, we identified KIR expression as a marker that distinguished 2 functionally and molecularly distinct γδ T cell subsets. KIR+ γδ T cells exhibited an advanced, memory-like differentiation state characterized by heightened cytotoxicity, stable epigenetic remodeling, and a predominant IFN-γ-producing profile. In contrast, KIR- γδ T cells maintained a naive-like phenotype and preferentially produced IL-17 upon polarization. Notably, KIR+ γδ T cells were consistently observed across individuals but were significantly enriched in cytomegalovirus (CMV)-seropositive donors, suggesting that chronic antigenic stimulation could promote the emergence of KIR+ effector γδ T cells. These findings reveal a functional dichotomy in human γδ T cells defined by KIR expression, linking IFN-γ-driven cytotoxicity with KIR+ cells and IL-17 production with KIR- cells. This insight advances our understanding of γδ T cell heterogeneity and has implications for viral immunity, immune memory, and the development of γδ T cell-based immunotherapies.