High CD26 and Low CD94 Expression Identifies an IL-23 Responsive Vδ2⁺ T Cell Subset with a MAIT Cell-like Transcriptional Profile

Vδ2⁺ T cells play a critical role in immunity to micro-organisms and cancer but exhibit substantial heterogeneity in humans. Here, we demonstrate that CD26 and CD94 define transcriptionally, phenotypically, and functionally distinct Vδ2⁺ T cell subsets. Despite distinct antigen specificities, CD26^hiCD94^lo Vδ2⁺ cells exhibit substantial similarities to CD26^hi mucosal-associated invariant T (MAIT) cells, although CD26⁻ Vδ2⁺ cells exhibit cytotoxic, effector-like profiles. At birth, the Vδ2⁺Vγ9⁺ population is dominated by CD26^hiCD94^lo cells; during adolescence and adulthood, Vδ2⁺ cells acquire CD94/NKG2A expression and the relative frequency of the CD26^hiCD94^lo subset declines. Critically, exposure of the CD26^hiCD94^lo subset to phosphoantigen in the context of interleukin-23 (IL-23) and CD26 engagement drives the acquisition of a cytotoxic program and concurrent loss of the MAIT cell-like phenotype. The ability to modulate the cytotoxic potential of CD26^hiCD94^lo Vδ2⁺ cells, combined with their adenosine-binding capacity, may make them ideal targets for immunotherapeutic expansion and adoptive transfer. Wragg et al. identify a population of human gd T cells with striking similarities to MAIT cells. These cells dominate the cord blood Vd2 population and upregulate an effector-like program upon antigen and IL-23 stimulation, providing a potential mechanism by which cytotoxic Vd2 cells may accumulate during adolescence and adulthood.