Distribution of granzyme-expressing NK cells in tuberculosis reflects subset and compartment-specific remodeling

Natural killer (NK) cells contribute to immunity against Mycobacterium tuberculosis (Mtb), yet their granzyme expression and subset distribution in TB remain poorly defined.

NK cell subsets and the expression of granzymes (GZMA, GZMB, and GZMK) and CCR5 were analyzed by multiparametric flow cytometry in peripheral blood from healthy controls, individuals with latent TB infection, active TB patients, and treated TB patients, as well as in paired pleural fluid samples.

In peripheral blood from active TB patients, NK cells exhibited reduced co-expression of GZMA, GZMB, and GZMK alongside decreased subset frequencies and absolute counts, a defect restored after treatment. In contrast, pleural fluid NK cells exhibited a distinct signature characterized by elevated GZMK but reduced GZMA and GZMB. This pattern was attributable to the relative enrichment of CD56^bright NK cells, which are inherently high in GZMK. We also identified a CCR5^bright NK cell subset, phenotypically resembling CD56^bright NK cells with high GZMK and low GZMA/GZMB expression, that was selectively expanded in peripheral blood of TB patients and enriched in pleural effusions. This subset was inducible by in vitro Mtb stimulation of healthy PBMCs.

These findings reveal granzyme remodeling and altered distribution of GZMK⁺CD56^bright NK cells associated with CCR5^bright expression in TB, suggesting their potential involvement in tissue-specific NK responses.