Background Natural killer (NK) cells respond to pathogen-infected and neoplastic cells by directly killing target cells and secreting immunoregulatory cytokines. Our understanding of the role of NK cells in tuberculosis (TB) pathogenesis remains incomplete.

Methods To gain a better understanding of peripheral blood NK cell functional changes that occur during progression to TB disease, NK cells were characterised using a CyTOF-based intracellular cytokine staining (ICS) assay in a cohort of Mycobacterium tuberculosis-exposed adolescents who were followed up over two years. To explore NK cell characteristics in human tissues, NK cells were also characterised in postmortem cohorts of TB patients who succumbed to disease, and non-TB controls who died from trauma. We characterised NK cell phenotypes and cytotoxic potential in postmortem samples from the lung, hilar lymph nodes, bronchoalveolar lavage (BAL), spleen, and peripheral blood mononuclear cells (PBMC).

Results Functionality scores (using Combinatorial Polyfunctionality analysis of Antigen-Specific Subsets – COMPASS) of peripheral blood NK cells were lower at distal timepoints from TB diagnosis in progressors relative to controllers. However, NK cell functionality scores of progressors increased significantly above controllers at timepoints closer to TB diagnosis. A cytokine neutralization assay suggested that peripheral NK cell cytokine and cytotoxic marker expression during TB disease were dependent on T cell bystander activation via IL-2. NK cells in peripheral blood of TB patients displayed mature, activated phenotypes, expressing higher levels of cytotoxic molecules than non-TB controls. In contrast, NK cells in tissues were phenotypically immature, and were particularly enriched in the lung of TB cases relative to non-TB controls.

Conclusion We observed marked differences and between peripheral blood and tissue NK cells, where enrichment of phenotypically immature and hypo-cytotoxic (expressing low levels of cytotoxic molecules) NK cells in the lung of TB cases potentially reflects a cause and/or consequence of disease pathogenesis, which requires further investigation.