Cytotoxicity Mechanisms Of

Pierre Golstein, Centre d'Immunologie INSERM-CNRS de Marsellle-Luminy, Marseille, France

Copyright © 1998 Elsevier Ltd. All Rights Reserved.

In 1960 Govaerts showed that white peripheral blood cells from alloimmune dogs were able to lyse in vitro target cells bearing the corresponding allo-antigens. Four decades and several thousands of publications later, we know that many different cell types have this ability to destroy other cells. This entry is conccrned, however, essentially with lymphoid cells (thus not touching in detail upon mechanisms of cytotoxicity by activated macrophages or by polymorphs, for instance). Among lymphoid cells, we consider mostly cytotoxic T lymphocytes. We briefly review, first their in vivo roles, then the phenomenology of cytoxicity, and finally molecular studies leading to the identification of two main mechanisms of T cell-mediated cytotoxicity as assessed in short-term in vitro assays, namely a mechanism involving granule exocytosis, perforin and granzymes, and a mechanism involving Fas and its ligand.

Why do cytotoxic cells exist at all? Under physiologic circumstances (i.e. not for instance in a situation of allograft rejection), they can meet and destroy only syngeneic cells. Since cells from a given organism usually cooperate rather than destroy each other, the selective advantage overriding this rule must be considerable. It is now believed that a main role of cytotoxic T cells is to lyse syngeneic cells presenting surface determinants originating from viruses or other intracellular microorganisms. These, when within cells, are out of reach of other immune system effectors. Destruction of infected cells destroys the microorganism or exposes it to other effector mechanisms. A teleological justification for the existence of T cell-mediated cytotoxicity, perhaps in particular perforin based, thus seems to be its role in fighting intracellular pathogens. Another in vivo counterpart, of in particular Fas-based cytotoxicity, is downregulation of immune responses, in part through recognition and destruction of Fas-bcaring activated lymphocytes. Neither the perforin- nor the Fas-based mechanisms in isolation, nor both together, seem to fully account for graft rejection. A possible role in spontaneous clinically significant tumor cell rejection is not clear; the therapeutic use against established tumors and their metastases of cytotoxic lymphokine-actived killer (LAK) cells or intratumor-derived cytolytic cells is still being investigated.

Another intriguing possibility, stemming from the finding that cytotoxic T cells recognize at the surface of target cells peptides which may derive from any protein (even intracellular), has been raised in particular by Thierry Boon's group in Brussels. A cell in which a given protein has been modified by somatic mutation would present at its surface correspondingly modified peptides. These would be recognized as foreign by the immune system. Activated cytotoxic T cells may consequently destroy the mutation-bearing cells. An important role of cytotoxic T cells might thus be to 'proofread' the genome against somatic modifications.

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