Mechanistic investigations of Granzyme A-mediated γ9δ2 T cell TB protective effects

Abstract One fourth of the world population is infected with Mycobacterium tuberculosis (Mtb). Currently, BCG strains are the only vaccines available to protect against tuberculosis (TB). Our lab has identified γδ T cells that secrete Granzyme A (GzmA) with TB protective effects. GzmA when released by TB-specific γδ T cells has been shown to inhibit the intracellular replication of the pathogen. To elucidate the mechanism(s) involved in this inhibition, the lab has purified human GzmA. The effects of this highly purified GzmA on mycobacterial replication inside human macrophages are being investigated using systems biology. A 2D-DIGE proteomic approach of PBMC-adherent cells has been performed to identify putative pathways involved in the control of mycobacterial replication. Our preliminary analysis of two PPD+ volunteers indicates that ER-stress responses (HSPA5, HSP90B1, P4HB, PDIA3) and purinergic channel receptor activation (ATP5B/C1/D/H/O) may be important for GzmA-mediated intracellular mycobacterial inhibition. Verification of these results is being performed to confirm the overall mechanism, and to exclude unrelated signals. Elucidation of the detailed pathways involved in pathogen clearance could lead to the development of novel chemotherapeutic and/or immunotherapeutic approaches for control of Mtb infection.