BCG vaccination induces antibacterial effector functions among Vδ1/3 T cells that are associated with protection against tuberculosis

γδ T cells expressing a Vδ1/3+ T cell receptor are enriched at mucosal surfaces, but their role in protection against Mycobacterium tuberculosis (Mtb) is largely unknown. We used multimodal single-cell RNA sequencing, mass cytometry, and flow cytometry to profile γδ T cells from human infants and macaques after protective vaccination with Mycobacterium bovis bacillus Calmette Guerin (BCG). A subset of Vδ1/3 T cells in BCG-vaccinated human infants shows evidence of clonal expansion and differentiation into Mtb-reactive cytotoxic effector cells. In macaques, intravenous BCG induces pro-inflammatory and cytotoxic responses to Mtb among Vδ1/3 T cells that are enriched in the airway compared to the blood. Finally, the frequency of cytokine-expressing Vδ1/3 T cells in the airway is associated with protection against Mtb challenge. Thus, Vδ1/3 T cells are activated by BCG and accumulate in the lung, where they upregulate cytotoxic and pro-inflammatory functions that may contribute to protective immunity against Mtb.