Carolyn A Cuff and Nancy H Ruddle, Department of Epidemiology and Public Health, Yale University, New Haven, Connecticut, USA

Lymphotoxin (LT, also known as TNFß) was originally described as a cytotoxic activity present in culture supernatants of activated lymphocytes. Ruddle and Waksman termed the material 'cytotoxic factor'; Granger and colleagues called it 'lymphotoxin'. In addition to its cytotoxic activity, LT appears to play a role in several biological processes. In vitro, LT induces gene expression of immune molecules such as major histocompatibility complex (MHC) and adhesion proteins, stimulates B cell growth, acts as an osteoclast-activating factor, and stimulates the replication of human immunodeficiency virus (HIV). In vivo, LT plays a critical role in lymphoid organ development, and has also been implicated in the pathogenesis of the autoimmune diseases multiple sclerosis and insulin-dependent diabetes mellitus. LT may also play a role in protection from infection.

It has recently been determined that LT can be produced as either a soluble protein or surface-associated protein. The soluble form of lymphotoxin is composed of three LTa monomers. It is produced after antigen activation of cytotoxic CD8 T cells and the Th1 subset of CD4 cells. It is also produced constitutively at a high level by several human T lym-photropic virus type I (HTI.V-I)-infected cell lines, by several murine malignantly transformed cell lines that represent early stages of B cell development, by human myeloma cells, and by human Epstein-Barr virus-transformed B cell lines. There have also been reports of its production by cells of the central nervous system, including astrocytes. LTa is not generally produced by macrophages. Analysis of the LToi genes and their proteins indicates strong conservation between several animal species with a homology of approximately 70% at the amino acid level of a secreted mature glycosylated protein of approximately 169 amino acids in length. The molecular weight of the LTot monomer is about 25 kDa, while the secreted trimeric complex is approximately 60-70 kDa in size.

In 1991, Browning and Ware and their colleagues determined that LT was expressed on the surface of T cells. Biochemical characterization of this surface form of LT indicated that LTa subunits associated with a 33 kDa type II transmembrane protein whose gene was subsequently cloned and called LT(3. The predominant form of the surface ET on T cells is a heterotrimer of one LTa subunit with two LT'|3 molecules (LTa,(32)- ET(3 mRNA is constitutively expressed by lymphocytes with the spleen and the thymus expressing the highest level of LTp in vivo. It appears that LTa expression is required for appropriate assembly and transport of LT0 to the cell surface. The LTa ,32 trimer possesses some cytotoxic activity although much less than LTa. It is not known whether an LTp, molecule exists and whether it possesses biologic activity.

LTa and LTp are also related to tumor necrosis factor a (TNFa), sharing sequence and structural characteristics as well as a tight genetic linkage. TNFa, LTa and LTa^ all bind to members of the TNF receptor family. These receptors are type I transmembrane proteins with cysteine-rich repeats in the extracellular domain. LTa and TNFa both bind to the type I (TNFRI) and type II (TNFRII) TNF receptors that are also referred to as p55 and p75 respectively. As noted above, because of its relatedness to TNFa and its common receptor usage with TNFRI and TNFRII, LTa is also termed TNFp. TNFa, after release by TNFa convertase (TACE), and LTa trimers bind to and cause clustering of the TNFRI and TNFRII receptors, and this clustering is important for transmission of a signal to the target cell. The crystal structure of the LTa trimer with TNFRI indicates that three receptors are bound by each trimer. LTa,p2 binds to the LTp receptor -originally called TNF receptor-related protein. A schematic representation of the TNF/LT ligand receptor system is shown in Figure 1.

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