Polycytotoxic T cells mediate antimicrobial activity against intracellular Mycobacterium tuberculosis

Protection against infections with intracellular bacteria requires the interaction of macrophages and T-lymphocytes, including CD8⁺ T cells. Recently, the expression of natural killer cell receptors NKG2A and NKG2C was introduced as markers of CD8⁺ T-cell subsets. The goal of this study was to functionally characterize human NKG2A and NKG2C-expressing T cells using the major pathogen Mycobacterium tuberculosis (Mtb) as a model organism. Sorted NKG2 populations were analyzed for their capacity to proliferate and degranulate and their intracellular expression of cytotoxic molecules. Cytokine release and the effect on bacterial growth were assessed after coculture of NKG2 populations with Mtb-infected macrophages. NKG2A⁺ T cells released higher levels of IFN-γ and IL-10, whereas NKG2C⁺ T cells released higher levels of IL-2, contained the greatest reservoir of intracellular granzyme B and showed a remarkable constitutive level of degranulation. Both subsets inhibited the intracellular growth of Mtb more efficiently than NKG2-negative CD8⁺ T cells. Antimicrobial activity of NKG2⁺ T cells was not associated with the release of cytokines or cytotoxic molecules. However, the frequency of polycytotoxic T cells (P-CTL), defined as CD8⁺ T cells co-expressing granzyme B, perforin, and granulysin, positively correlated with the ability of NKG2-expressing T cells to control Mtb-growth in macrophages. Our results highlight the potential of NKG2-expressing P-CTL to trigger the antibacterial activity of human macrophages. Targeting this population by preventive or therapeutic immune interventions could provide a novel strategy to combat severe infectious diseases such as tuberculosis.