Target cell apoptosis induced by cytotoxic T cells and natural killer cells involves synergy between the pore-forming protein, perforin, and the serine protease, granzyme B.
Cytotoxic lymphocytes (CL) comprise two effector cell populations with the ability to eliminate unwanted or harmful cells. Cytotoxic T cells (CTLs) demonstrate both an exquisite specificity and memory in recognising target cell oligopeptides presented within the groove of major histocompatibility complex class I antigens. By contrast, natural killer (NK) cells mediate "innate' immunity against virus-infected cells and surveillance against neoplastic transformation, and do not require presensitisation. Despite recognising target cells in very different ways, CTLs and NK cells both utilise a pore-forming protein, perforin, and a battery of serine proteases as a principal means of inflicting cell death. The action of both types of CL results in death by apoptosis. Recently, we and others have accumulated evidence that perforin and serine proteases synergistically trigger an endogenous pathway of programmed cell death that results in dissolution of the nuclear membrane, chromatin condensation and DNA fragmentation. These changes are secondary to inappropriate activation of p34, a kinase whose activation and migration from the cytoplasm to the nucleus normally controls a cell's entry into mitosis. Therefore, CI, may exert their actions through the derangement of cell cycle control. The downstream molecular targets of perforin/granzyme-mediated apoptosis (especially the physiological ligand/substrate of granzyme B) are still unclear, though candidate molecules with homology to products of cell death genes found in primitive organisms such as the nematode, C. elegans, are currently under investigation.
Trapani
J A
JA
Cellular Cytotoxicity Laboratory, Austin Research Institute, Melbourne, Vic.
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D004249:DNA Damage / Q000276:immunology; D053804:Granzymes; D006801:Humans; D007157:Immunologic Surveillance / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008211:Lymphocyte Cooperation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000502:physiology*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases