Noncytotoxic functions of granzymes in inflammation and antiviral immunity

Abstract

Cytotoxic lymphocytes, including cytotoxic (CD8+) T lymphocytes, natural killer (NK) cells, NKT, and gamma delta (γδ) T cells, play crucial roles in inflammation, antitumor, and antiviral immunity. Upon activation, cytotoxic lymphocytes mainly employ the granule exocytosis pathway to destroy target cells. They release a pore-forming protein perforin and a family of five structurally homologous serine proteases called granzymes (GrA, GrB, GrH, GrK, and GrM) that display distinct substrate specificities towards target cells. Perforin makes pores in the cellular membrane to facilitate entry of granzymes into target cells, where granzymes can exert intracellular functions, such as inducing cell death and noncytotoxic viral inhibition. In addition, granzymes can also exist extracellularly, where they perform proinflammatory functions and extracellular matrix modification. In this thesis, we have unraveled extracellular roles of granzymes in inflammation, including proinflammatory role of extracellular granzymes in the pathogenesis of rheumatoid arthritis and a novel proinflammatory role of GrA. In addition, we also investigated intracellular noncytotoxic functions of granzymes in antiviral immunity. We show that cytotoxic cells can control HCMV infection in a noncytotoxic manner via targeting indispensable viral proteins and restore cGAS-STING signaling and host cell IFN-β response during HCMV infection. At last, we developed a specific granzyme sensor which provides a potentially beneficial tool to investigate cytotoxic cell-target cell interactions and their spatiotemporal dynamics.