Immunity, Granzymes and Cell Killing

Abstract Cytotoxic lymphocytes protect us from viral infection and cancer by directly killing tumour cells or cells harbouring a virus. One crucial mechanism they use to kill their targets is known as the ‘granule exocytosis’ pathway. This involves secretion of a potent mix of toxins, resulting in transfer of granule proteases (granzymes) from the killer cell into the target cell, where they cleave various intracellular substrates to activate diverse signalling pathways to cell death. Access to the target cell cytosol depends on a pore‐forming protein toxin, perforin. Because granule exocytosis is a crucial part of the body's natural defence against such dangerous cells, understanding how granzymes kill their targets may yield novel strategies and identify new molecular targets for anticancer or antiviral therapies. Indeed, recent advances in cancer immunotherapy such as checkpoint blockade and adoptive transfer of chimeric antigen receptor (CAR) T cells all ultimately rely on activating the granule exocytosis pathway to kill cancer cells. Key Concepts The critical role of cytotoxic T lymphocytes and natural killer cells is to eliminate abnormal cells, thereby defending higher organisms against intracellular infection. An important additional function of cytotoxic lymphocytes also encompasses their role in surveillance against transformed cells. Perforin and granzymes synergise to kill target cells. Perforin is critical to this process and its role is to enable granzyme proteases to access key substrates in the target cell. Perforin functions by punching large pore‐like defects in the target cell membrane, permitting direct granzyme diffusion into its cytosol. Granzyme B is the most potent proapoptotic granzyme, as it shares with caspases the capacity to cleave its substrates after key aspartate residues. Cytotoxic lymphocytes have developed a plethora of different signalling pathways to bring about target cell death. This is critically important as viruses are adept at blocking cell death to maximise their opportunity for viral replication and spread to uninfected cells. These granzyme‐dependent cell death pathways are mechanistically distinct and arranged in a hierarchy in terms of their potency and kinetics. Apart from inflicting cell death, granzymes have additional functions such as directly interfering with viral replication and in cytokine processing, leading to amplification of the inflammatory response to pathogens. Dysregulation of cytotoxic T‐cell function can sometimes lead to adverse effect such as autoimmune tissue damage.