TIGIT blockade improves anti-Mycobacterium tuberculosis immunity

Despite the therapeutic benefit of immune checkpoint blockade in cancers, there is no consensus on its effect in infectious diseases. Here we investigated whether blocking the immune checkpoint T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) increases T cell immunity in active Mycobacterium tuberculosis infection. TIGIT expression in both peripheral blood and lung lesions in tuberculosis patients was assessed, and the correlation with clinical features analyzed. The functional status of TIGIT+ and TIGIT-CD8+ T cell subsets in tuberculosis patients was analyzed by flow cytometry and transcriptome analysis. To investigate the regulatory effect of TIGIT, the function of CD8+ T cells in tuberculosis patients and bacterial load in a tuberculosis mouse model were assessed after in vitro and in vivo TIGIT blockade. In active tuberculosis patients, TIGIT expression on CD8+ T cells in the peripheral blood was significantly upregulated and positively correlated with disease severity. TIGIT expression in lung lesions was significantly higher in patients with pulmonary tuberculosis than in patients infected with other pathogens. TIGIT+CD8+ T cells exhibited higher activation and differentiation levels, increased expression levels of cytokines and cytotoxic molecules, and showed gene expression features of natural killer-like cytotoxic effector CD8+ T cells. TIGIT blockade increased the ability of human CD8+ T cells to produce effector molecules and kill intracellular bacteria in vitro. Importantly, blocking TIGIT reduced lung bacterial burden in mice infected with M. tuberculosis. The findings reveal that in active tuberculosis patients, activated CD8+ T cells express TIGIT and blocking TIGIT enhances CD8+ T cell function and promotes clearance of M. tuberculosis. The findings also suggest that TIGIT limits T cell immunity in tuberculosis and implicate TIGIT blockade as a novel strategy for tuberculosis therapy.