Enrichment of CD4−CD8− cytotoxic Vδ1/3 T cells in pulmonary tuberculosis disease

Tuberculosis (TB), caused by Mycobacterium tuberculosis ( Mtb ), remains a leading cause of global morbidity and mortality. Although gamma-delta (γδ) T cells have increasingly been suggested to contribute to the TB immune response, quantitative and qualitative differences in this immune cell compartment between healthy and diseased individuals are not well-characterized. In this study, we used single-cell RNA sequencing to provide a high-resolution characterization of CD4 − CD8 − γδ T cells in peripheral blood across healthy Mtb -(non-)sensitized and TB disease pre-/post-treatment cohorts. We found an activated and cytotoxic gene signature in γδ T cells of TB disease compared with both healthy cohorts. Strikingly, these differences persisted through 1 year following TB disease diagnosis. These transcriptomic differences were largely mediated by an NK-like cytotoxic Vδ1 and Vδ3 subset that was enriched in TB disease. Our findings suggest long-lasting changes in the CD4 − CD8 − γδ T cell compartment and highlight specific subsets as potentially important in TB.