Lymphotoxins: from cytotoxicity to lymphoid organogenesis.

Abstract

Tumor necrosis factor (TNF) and lymphotoxins (LT) belong to a family of structurally related cytokines (1) that were originally recognized for their cytotoxic effects on normal or transformed cells (2–4). The genes for the lymphotoxins α (LTα) and β (LTβ) as well as for TNF are clustered within the major histocompatibility complex (5–7). Whereas TNF can be expressed and secreted by a variety of cells including lymphocytes, NK cells, and monocytes (1), the lymphotoxins are mostly produced by activated lymphocytes and NK cells (8). TNF exists as a homotrimer that interacts with two TNF receptors, p55 TNFR and p75 TNFR. The lymphotoxins can be found either as homotrimers or heterotrimers. The LTα homotrimer lacks a transmembrane domain. The LTα,β2 heterotrimer can be retained at the cell surface because LTβ is a type II transmembrane protein (6). The LTα homotrimer binds like TNF to the p55 TNF and p75 TNF receptors (6), whereas the LTα,β2 heterotrimer binds to the LTβ receptor (3) (Fig. 1). The p55 and p75 TNF receptors are expressed in a variety of tissues including hemopoetic and epithelial cells (9). LTβ expression is found in primary and secondary lymphoid tissues but is absent in cells of peripheral blood (9). Figure 1 TNF, LT, and their receptors. A number of studies in mice deficient in either TNF or LT as …