Loss of circulating CD8α ⁺ NK cells during human <i>Mycobacterium tuberculosis</i> infection

Abstract Natural Killer (NK) cells can recognize and kill 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 (IGRA-contacts) with a progressive loss of these circulating cells during household-associated latent infection and 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 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.