Mycobacterium tuberculosis Modulates the Expansion of Terminally Exhausted CD4+ and CD8+ T-Cells in Individuals with HIV-TB Co-Infection

Introduction: Mycobacterium tuberculosis (Mtb), the most common co-infection among people living with HIV (PLWH), aggravates the associated morbidity and mortality in these individuals; however, the immune-modulatory role of Mtb in the pathogenesis of HIV infection remains incompletely understood. Methods: We investigated the role of Mtb infection in regulating adaptive immune responses with reference to the expression of five immune checkpoint molecules (ICMs) in co-infected individuals in a cross-sectional study conducted on treatment-naïve human cohorts from North India, including PLWH, people with Mtb infection, people with HIV-Mtb co-infection, and healthy volunteers as controls. Results: The data revealed a significantly increased gene expression of TIM-3 (p = 0.0058), LAG-3 (p < 0.0001), PD-1 (p = 0.0090), and CTLA-4 (p = 0.0008). It also revealed a higher frequency of CD4+ and CD8+ T-cells surface-expressing TIM-3+, CTLA-4+, LAG-3+. Finally, it showed cells co-expressing two ICMs together (p < 0.05) in individuals with HIV–Mtb co-infection as compared to HIV mono-infected ones. Interestingly, the frequency of these cells correlated inversely with the absolute CD4+ T-cell count and positively with the plasma viral load (p < 0.05), indicating direct association with HIV disease progression. Conclusions: These findings suggest that Mtb co-infection exacerbates immune exhaustion in co-infected individuals. Targeting ICMs with pharmacological immune checkpoint inhibitors (ICIs) offers a promising approach for better clinical management of co-infected individuals.