Killer cell immunoglobulin-like receptors delineate distinct phenotypes and functions in human γδ T cells [RNA-seq]

Killer cell immunoglobulin-like receptors (KIRs) are a diverse family of HLA class I-specific receptors that shape immune responses, primarily through NK cells. Beyond NK cells, subsets of T cells, notably γδ T cells, express KIRs, but their roles remain unclear. Here, we demonstrate that KIR⁺γδ T cells are significantly more abundant in CMV-seropositive healthy adults, particularly within the Vδ2⁻ subset. These cells exhibit a TEMRA phenotype, are predominantly CD16⁺CD57⁺, hallmarks of a highly differentiated state, and express multiple NK cell-associated receptors. KIR+γδ T cells display enhanced cytotoxic potential, with higher levels of granzyme B and perforin than their KIR- counterparts. Using Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) and transcriptional analyses, we show that KIR- and KIR+ γδ T cells reveal distinct molecular signatures, with KIR+γδ T cells transcriptionally and epigenetically aligning with terminally differentiated effector memory T cells, while KIR- cells retain a naïve-like phenotype. These findings suggest that CMV infection drives the differentiation of γδ T cells into potent, KIR-expressing cytotoxic effectors. This adaptive mechanism may bolster immune defense while maintaining self-tolerance, highlighting a previously unappreciated role for KIRs in shaping γδ T cell immunity.