Lymphotoxin: Properties, role and mode of action

Abstract

About twenty years ago, studies by Govaerts (1960), Rosenau & Moon (1961) and Rosenau (1963) showed that aggressor lymphocytes from specifically sensitized animals establish direct contact with allogeneic target cells in vitro, which is followed by target-cell lysis. These findings pointed to the essential role of such lymphocytes in cellular immune reactions characterized by cell or tissue destruction. It was subsequently established that the cytotoxic cells are T lymphocytes, which react with specific target cells (Cerrottini, Nordin & Brunner, 1970). Cell lysis appears to proceed in two steps. First, the lymphocytes establish contact with the target cells. This reaction is Ca 2+and Mg2÷-dependent, but fairly independent of temperature (Berke, Sullivan & Amos, 1972; Martz, 1975. The second step does not require the presence of lymphocytes and proceeds effectively only at temperatures near 37°C (Martz & Benecerraf, 1974). Complement does not appear to be involved. For several years, the mechanism of lymphocytemediated lysis remained totally obscure. Ruddle & Waksman (1968), working with lymphocytes derived from tuberculin-sensitized rats, observed a cytotoxic factor in culture supernatants upon addition of purified tuberculoprotein (PPD). That same year, Granger & Williams (1968) found cytotoxic activity in lymphocyte cultures stimulated with the mitogen phytohemagglutinin (PHA). The substance responsible for the cytotoxicity was first called lymphocyte cytotoxic factor, but the term lymphotoxin (LT) subsequently came into general use. Lymphotoxin does not possess target-cell specificity, except that one form, the LT complex, has been reported to associate with immunoglobulin, and may thus perhaps gain specificity (see below). Several investigators have suggested that the specificity of the cytotoxic reaction is related to the ability of specifically sensitized T lymphocytes to recognize and attach themselves to target cells; they then discharge the nonspecific cytotoxin (LT) that accomplishes target-cell lysis. Almost all of the observations on LT have been made in vitro, and there is little information on this lymphocyte mediator (lymphokine) in the intact organism. Two previous reviews have dealt with certain aspects of LT (Rosenau & Tsoukas, 1976; Gately & Mayer, 1978).