The Binding and Lysis of Target Cells by Cytotoxic Lymphocytes: Molecular and Cellular Aspects

Abstract

The characteristics of cytotoxic T lymphocyte (CTL) and natural killer (NK) cell recognition of and binding to target cells (conjugate formation), and the precise mechanism(s) by which the target cells are triggered to undergo apoptotic cell lysis are now being deciphered at the cellular and molecular levels. Involvement of a multitude of cell surface molecules, in addition to T cell receptor (TCR)-major histocompatibility (MHC)-peptide complexes, in the binding and signalling for lymphocyte-mediated lysis has been demonstrated. Two proposed mechanisms of lymphotoxicity currently appear to be valid: (i) a membranolytic one initiated by the formation of pores in target cell membranes by secreted molecules of lymphocyte origin, such as perforin and granzymes, and (ii) a nonsecretory one initiated by receptor-mediated triggering of apoptosis-inducing target cell surface molecules, but not involving the secretion of pore-forming agents and granzymes. Perforin and granzymes are probably involved in lymphocyte activation and are likely mediators of the membranolytic pathway of lymphotoxicity. Existence of the nonsecretory and receptor-triggered lytic mechanism was indicated by (i) the prelytic fragmentation of the target cell's DNA, which precedes release of intracellular (51Cr-labeled) components, (ii) the demonstration of cytolytic effector cells that are either devoid of or express background levels of lytic granules and perforin, and (iii) the observation that some CTL lyse target cells under conditions at which perforin and granzymes are neither secreted nor lytic, e.g. [Ca2+]o < 1 micromolar. These two mechanisms are not mutually exclusive and are probably used by different types of effector cells or by the same effector cells at different stages of differentiation. In fact, recent perforin gene knock-out experiments support the existence of both.

Suppression of apoptosis by bcl-2 does not prevent p53-mediated control of experimental metastasis and anchorage dependence

“…Apoptosis is a strong selective factor for tumor cells since it determines cell sensitivity to hypoxia (Graeber et al, 1996), immunocyte attack (Pross and Lotzova, 1993;Berke, 1994), factors released by endothelial cells (Dong et al, 1994), chemo-and radiation therapy (Lowe et al, 1994) and by deprivation from contacts with the natural microenvironment (Nikiforov et al, 1996). We analysed whether a metastasis suppressor function of p53 is equivalent to the execution of apoptosis.…”

c-Myc and E1A induced cellular sensitivity to activated NK cells involves cytotoxic granules as death effectors

“…The¯uorescence microscopy of phalloidin-stained, target bound NK cells revealed prominent actin polymerization to Factin form at the cell-cell contact sites (Figure 3b). The actin polarization, which indicates the cytolytic activation of killer cells (Berke, 1994;Gri ths, 1995), was commonly found also in NK cells bound to Rat1 cells, which were resistant to NK cell-induced death ( Figure 3b). Next, we measured the amount of cellular inositolphosphates whose increased generation by phosphoinositide hydrolysis occurs during the exocytosis of the cytotoxic granules (Atkinson et al, 1990;Chow and Jondal, 1990;StaÊ hls and Carpen, 1989).…”

“…Triggering of NK cell cytolytic machinery results in the directed exocytosis of cytotoxic granules (Berke, 1994). These granules are the primary mediators of NK cell cytotoxicity, and the major granule components involved in the cytotoxic process are a membrane poreforming protein called perforin and serine proteases called granzymes.…”

Activated CD4+CD25+ T cells selectively kill B lymphocytes

“…The Fas/FasL pathway has been described as an important regulator of T-and B-lymphocyte population size and function in vivo [23][24][25] and it has been established as one of the main lytic mechanisms to maintain lymphocyte homeostasis. 26,27 Figure 3A). Furthermore, the proliferative response of Fas-deficient B cells from MRL/lpr mice was suppressed to the same extent as that of wild-type (WT) B cells ( Figure 3B).…”