Transcriptional profiling of human Vδ1 T cells reveals a pathogen-driven adaptive differentiation program

γδ T cells are generally considered innate-like lymphocytes, however, an “adaptive-like” γδ compartment has now emerged. To understand transcriptional regulation of adaptive γδ T cell immunobiology, we combined single-cell transcriptomics, T cell receptor (TCR)-clonotype assignment, ATAC-seq, and immunophenotyping. We show that adult Vδ1⁺ T cells segregate into TCF7⁺LEF1⁺Granzyme B^neg (T_naive) or T-bet⁺Eomes⁺BLIMP-1⁺Granzyme B⁺ (T_effector) transcriptional subtypes, with clonotypically expanded TCRs detected exclusively in T_effector cells. Transcriptional reprogramming mirrors changes within CD8⁺ αβ T cells following antigen-specific maturation and involves chromatin remodeling, enhancing cytokine production and cytotoxicity. Consistent with this, in vitro TCR engagement induces comparable BLIMP-1, Eomes, and T-bet expression in naive Vδ1⁺ and CD8⁺ T cells. Finally, both human cytomegalovirus and Plasmodium falciparum infection in vivo drive adaptive Vδ1 T cell differentiation from T_naive to T_effector transcriptional status, alongside clonotypic expansion. Contrastingly, semi-invariant Vγ9⁺Vδ2⁺ T cells exhibit a distinct “innate-effector” transcriptional program established by early childhood. In summary, adaptive-like γδ subsets undergo a pathogen-driven differentiation process analogous to conventional CD8⁺ T cells.