CD8α marks a Mycobacterium tuberculosis-reactive human NK cell population with high activation potential.

Natural Killer (NK) cells can recognize and kill Mycobacterium tuberculosis (Mtb)-infected cells in vitro, however their role after natural human exposure has not been well-studied. To identify Mtb-responsive NK cell populations, we analyzed the peripheral blood of healthy household contacts of active Tuberculosis (TB) cases and source community donors in an endemic region of Port-au-Prince, Haiti by flow cytometry. We observed higher CD8α expression on NK cells in putative resistors (Interferon γ release assay negative; IGRA- contacts) with a loss of CD8α surface expression during household-associated exposure and active TB disease. In vitro assays and CITE-seq analysis of CD8α NK cells demonstrated enhanced maturity, cytotoxic gene expression, and response to cytokine stimulation relative to CD8α NK cells. CD8α NK cells also displayed dynamic surface expression dependent on MHC class I in contrast to conventional CD8 T cells. Together, these results support a specialized role for CD8α NK cell populations during Mtb infection correlating with disease resistance.