Overview of pathways for cellmediated cytotoxicity

T cell-mediated cytotoxicity in short time assays (3-4 h) is achieved through two main mechanisms. A first mechanism, Ca2+ dependent, requires the action of the pore-forming protein perforin and a subfamily of serine proteases named granzymes or fragmentins (1). The second mechanism, which is Ca2+ independent for its execution, requires the expression of Fas (Apo-l/CD95) at the target cell surface (2), and of the Fas ligand (FasL) at the effector cell surface (3). The fact that the residual cytotoxic activity detected in T cells from perforin knock-out mice could be attributed solely to Fas-based cytotoxicity underscored the importance of these two lytic mechanisms (4)

Perforin and granzymes are only expressed in specialized killer cells like cytotoxic T lymphocytes (CTL) or natural-killer (NK) cells, where they are stored in secretory granules (5, 6). After the recognition by CTL or NK cells of a virus-infected or a tumour cell, these granules are secreted and the perforin-mediated entry of granzymes into the cytoplasm causes the rapid lysis of target cells (4, 7). Although also implicated in CTL- and NK-induced lysis, the main physiological role of Fas-based cytotoxicity may be the control of peripheral tolerance (8, 9). The implication of Fas-based cytotoxicity in activation-induced cell death (AICD) of T cell hybridomas (10) and of normal T cell blasts (11) has been clearly demonstrated. It has been suggested that tumour necrosis factor-a (TNF) mediates AICD of CD8+ T cells in the absence of Fas expression, while the Fas/FasL system would be the main cause for AICD of CD4+ T cells (12). These results suggest that T cells able to secrete TNF could use this cytokine for the lysis of target cells expressing TNF receptors. It should be noted, however, that TNF-induced toxicity is usually detected only after long incubation times (48-72 h) (12).

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