Immune escape through NKG2A upregulation in tuberculosis: Single-cell and functional evidence for therapeutic blockade

The mechanisms of immune escape that impede an effective immune response and lead to immune cell depletion in tuberculosis infection remain an unsolved problem. However, blocking NKG2A, an inhibitory receptor, has been shown to activate and enhance the function of cytotoxic lymphocytes, which has shown efficacy in tumor immunotherapy and may provide new ideas for the immunotherapy of tuberculosis. Here, we integrate single-cell data on tuberculosis infection along with clinical cohort and flow cytometry analyses and show that KLRC1-encoded NKG2A is significantly upregulated in T and NK cells from patients with active tuberculosis. These cells with high KLRC1 expression exhibited an exhaustion phenotype, as indicated by impaired cell activation, reduced secretion of toxic granules, and decreased metabolic activity. Notably, functional blockade of NKG2A restored immune activity: T cells enhanced MPEG1 and granzyme A expression, whereas NK cells upregulated iNOS, TRAIL, granzyme B, and CD107a. Mechanistically, NKG2A inhibition reactivates the Ras-p38/AKT signaling pathway in NK cells, promotes binding to infected macrophages, and supports a matched cytotoxic profile by reducing ROS and enhancing mitochondrial metabolism. Importantly, NKG2A blockade enhanced bacterial clearance in PBMCs from TB patients. These findings identify NKG2A as a key immune checkpoint mediating cytotoxic dysfunction in tuberculosis and support its blockade as a strategy to restore the host antimicrobial response.