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, CD26CD94 Vδ2 cells exhibit substantial similarities to CD26 mucosal-associated invariant T (MAIT) cells, although CD26 Vδ2 cells exhibit cytotoxic, effector-like profiles. At birth, the Vδ2Vγ9 population is dominated by CD26CD94 cells; during adolescence and adulthood, Vδ2 cells acquire CD94/NKG2A expression and the relative frequency of the CD26CD94 subset declines. Critically, exposure of the CD26CD94 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 CD26CD94 Vδ2 cells, combined with their adenosine-binding capacity, may make them ideal targets for immunotherapeutic expansion and adoptive transfer.