Profiles of cytotoxic granules in memory CD8 T cells correlate with function, differentiation stage and antigen exposure

Evaluation of: Harari A, Enders FB, Cellerai C et al: Distinct profiles of cytotoxic granules CD8 T cells correlate with function, differentiation stage, and antigen exposure. J. Virol 83(7), 2862-2871 (2009). The likely main effector function by which CD8+ T cells exert their role in the immune surveillance of infected and tumorogenic cells is mediated by the production of cytokines and cytotoxic secretory granules. These cytolytic activities complement ligand-mediated mechanisms of cell death, including Fas/Fas ligand-induced apoptosis. The cytotoxic granules contain perforin, which destabilizes the cell membrane of the target cell and proteases, specifically granzymes (Grms), which once have entered the target cell, provoke rapid cell death. There are currently five different Grms known that are referred to as Grms A, B, H, K and M. Despite some detailed studies, their respective role in the different stages of the cytotoxic process is poorly understood. Harari and colleagues have analyzed the expression of three Grms (i.e., Grms A, B and K) in CD8, T cells specific for influenza virus, Epstein-Barr virus, cytomegalovirus and HIV-1. Their results describe differential expression patterns of perforin, Grm 6 and Grm K, depending on the virus specificity of the cytotoxic T lymphocytes. Analyses of the T-cell maturation phenotypes revealed a direct correlation between the differentiation stage of the memory T cells and the expression of perforin, Grm B and Grm K. Linking the differentiation phenotype with different viral infections indicated that antigen persistence is a driving force behind the variable Grm composition of the cytolytic granules. The data also associate a differential cytotoxic pattern with the different differentiation stages of the virus-specific memory CD8+ T-cell populations, thus providing a much improved understanding of how antigen persistence, T-cell differentiation and maturation, as well as cytolytic effector functions are interlinked.