Killer Cell Immunoglobulin-Like Receptors Delineate Distinct Phenotypes and Functions in Human γδ T Cells

Abstract

Human circulating γδ T cells are broadly classified into three subsets: Vδ1, Vδ2, and Vδ1/2neg populations, with the Vδ2 subset being the most abundant. In this research, I focus on the contribution and interplay of Natural Killer (NK) receptors to the γδ T cell phenotype and function, with emphasis on Killer-cell Immunoglobulin-like Receptors (KIRs), which are poorly studied in the field of γδ T cell biology. Because cytomegalovirus (CMV) is known to shape the αβ T cell and NK cell repertoires, I studied peripheral blood (PB) γδ T cells from both CMV-seronegative (CMV-) and CMV-seropositive (CMV+) healthy adult humans, using spectral flow cytometry. I found that CMV leaves a stable imprint in the γδ T cell repertoire and phenotype. CMV+ individuals have increased proportions of Vδ1 T cells within the total γδ T cell population. Moreover, γδ T cells from these individuals display increased proportions of cells expressing KIRs, which constitute a highly polymorphic family of receptors for Human Leukocyte Antigen (HLA) class I. These KIRs delineate a dichotomy in the phenotype and function of γδ T cells. KIR+γδ T cells exhibit characteristics akin to memory like T cells, displaying heightened effector potential, whereas KIR-γδ T cells resemble naïve T cells with comparatively weaker immune responses. Leveraging the assay for transposase-accessible chromatin with sequencing (ATACseq) technology, I show that KIR+γδ T cells have more open loci associated with effector functions than KIR-γδ T cells, which is consistent with the above results. These findings underscore a critical role for KIRs in γδ T cell immunity and hold implications for both our understanding of immune responses influenced by CMV and the potential of γδ T cells in cellular immunotherapy.