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CD8 + T cells contribute to tuberculosis (TB) infection control by inducing death of infected macrophages.  Mycobacterium tuberculosis  ( Mtb ) infection is associated with increased PD-1/PD-L1 expression and alternative activation of macrophages. We aimed to study the role of PD-1 pathway and macrophage polarization on  Mtb -specific CD8 + T cell-induced macrophage death. We observed that both PD-L1 on CD14 +  cells and PD-1 on CD8 + T cells were highly expressed at the site of infection in pleurisy TB patients’ effusion samples (PEMC). Moreover, a significant increase in CD8 + T cells’  Mtb -specific degranulation from TB-PEMC vs. TB-PBMC was observed, which correlated with PD-1 and PDL-1 expression. In an  in vitro  model, M1 macrophages were more susceptible to  Mtb -specific CD8 + T cells’ cytotoxicity compared to M2a macrophages and involved the transfer of cytolytic effector molecules from CD8 + T lymphocytes to target cells. Additionally, PD-L1 blocking significantly increased the  in vitro  Ag-specific CD8 + T cell cytotoxicity against IFN-γ-activated macrophages but had no effect over cytotoxicity on IL-4 or IL-10-activated macrophages. Interestingly, PD-L1 blocking enhanced  Mtb -specific CD8 +  T cell killing of CD14 +  cells from human tuberculous pleural effusion samples. Our data indicate that PD-1/PD-L1 pathway modulates antigen-specific cytotoxicity against M1 targets  in-vitro  and encourage the exploration of checkpoint blockade as new adjuvant for TB therapies.

PD-1/PD-L1 Pathway Modulates Macrophage Susceptibility to Mycobacterium tuberculosis Specific CD8+ T cell Induced Death