B144

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Figure 4 Genetic map of the tumor necrosis factor/lymphotoxin (TNF/LT) locus in the human MHC. (Reproduced with permission from Ware et al (1995) In: Griffiths and Tschopp (eds) Pathways for Cytolysis, pp 175-218. Basel: Springer-Verlag.)

Figure 4 Genetic map of the tumor necrosis factor/lymphotoxin (TNF/LT) locus in the human MHC. (Reproduced with permission from Ware et al (1995) In: Griffiths and Tschopp (eds) Pathways for Cytolysis, pp 175-218. Basel: Springer-Verlag.)

receptors found on individual cells range from 2000 to 50 000. Though the presence of a receptor is required for a response to LTa, the number of molecules expressed by a cell does not necessarily reflect its sensitivity to LTa. Nevertheless, susceptibility to killing by LTa can be enhanced by treatment of targets with IFNy and this does result in increased binding of LTa, presumably due to increased numbers of receptors.

Less is known about the properties of the LT(3R. LT(3R mRNA has been detected during embryo-genesis as well as in the lung, kidney, liver, spleen and lymph node of the adult mouse, and in several tumor cell lines. The expression of LT(3R during embryogenesis suggests it may mediate a signal for lymphoid organ development through binding to the LTa jpt complex. It is also possible that an as yet unidentified receptor for LTa also plays a role in lymphoid organ development.

Several intracellular signaling events have been implicated in the TNF/LT pathway, including protein kinases, ceramide, proteases, lipases and induction of gene transcription. However, since the TNF receptors contain no intrinsic enzymatic activity, it has been difficult to determine the intracellular events that occur following ligand binding. Recently, regions of the TNFRI, TNFRII and the LT(3 receptor have been identified that are necessary for the transmission of signal to the target cell. An 80 amino acid region in TNFRI is necessary for the cytotoxic activity of TNF. This region has been termed the 'death domain' and is also found in other members of the TNF receptor family that mediate apoptosis. An intracellular protein, TRADD, has also been identified that binds to the TNFRI through the death domain and initiates the cytotoxic activity. TNFRII and LT(BR similarly possess regions in their cytoplasmic tails that bind intracellular proteins involved in the signal cascade. Both of these receptors bind to proteins called TRAFs. The TRAF (TNFR-associated factor) proteins associate with the receptor and form an intracellular complex that activates NFkB and subsequent gene expression.

In conclusion, the role of LT in biological processes is quite complex and not fully understood. Its expression is required for the development of lymphoid organs and contributes towards the elaboration of inflammatory processes that are essential for clearance of infectious agents. However, LT expression can also be harmful, contributing towards the pathogenesis of autoimmune diseases. It thus appears that the effects of LT in vivo may depend upon appropriate expression levels at the correct time in development or during immune responses. The generation of mice deficient in LTa has allowed for the characterization of the role of LT in immune function as well as its contribution towards autoimmunity. Further data with LT(3-deficient mice will provide information regarding the individual roles of secreted LTa and the membrane-associated LTa/(3 complex.

See also: Cytokine assays; Cytokine genes, regulation of; Cytokines; Cytokine receptors; Cytotoxic T lymphocytes; Cytotoxicity, mechanisms of; Effector lymphocytes; Experimental autoimmune encephalomyelitis (EAE); Graft rejection; Graft-versus-host reaction; Lymphokine-activated killer (LAK) cells; Tumor necrosis factor a.

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