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.