Biologic roles

The role of LTa in lymphoid organ development was established through the analysis of mice made deficient in that protein through homologous recombination. LTa-deficient mice are completely devoid of peripheral and mesenteric lymph nodes (Figure 2) as well as Peyer's patches. Though the thymus appears normal, there is marked splenic disorganization with a loss of T and B cell areas and germinal centers. It has not yet been established whether LT exerts its effects on lymphoid organ development through the secreted LTa trimer or through the surface-associated LTa/p complex. It has been assumed by some authors that LT exerts its effects in lymphoid development as an LTa/p complex because both TNFRI- and TNFRII-deficient mice have normal lymph nodes. This invokes a role for another receptor, which could be I.TpR. An alternative explanation is that there is another LT-specific receptor which has not yet been identified. The role of LTp in lymphoid development will be revealed with the analysis of LTp-deficient mice. However, the organization of lymphoid tissue is probably quite complex, involving several TNF family members and their receptors. This is evidenced by the TNFRI-deficient mice who, although they have normal lymph nodes, lack Peyer's patches and germinal centers.

LT also plays a role in the initiation and elaboration of inflammation. LTa mRNA has been detected during several inflammatory processes in humans and mice. Its proinflammatory properties arc-most clearly demonstrated in a transgenic mouse model in which LTa is expressed in the pancreas under the control of the rat insulin promoter (RIP). These mice contain leukocytic infiltrates around the pancreatic islets - the site of transgene expression (Figure 3). The mechanism of the LT-induced mononuclear accumulation includes induction of adhesion proteins on the surface of endothelial cells that facilitate the egress of leukocytes to the site of transgene expression and may also involve the induction of

Mice Lymph System
Figure 1 Schematic of TNF/LT ligand receptor system.
Figure 2 LTa-deficient mice lack lymph nodes. (A) Lymph node of a normal mouse. (B) The same region of an LTa-deficient mouse that lacks lymph nodes. (Reproduced with permission from De Togni etal (1994) Science 264: 703-707. © 1994 American Association for the Advancement of Science.)

chemokines that chemotactically recruit lymphocytes.

LTa is a mediator of killing by cytolytic T cells, 'helper-killer' T cells, natural killer cells, and lymphokine-activated killer cells. It is produced by such cells after stimulation by antigen presented by MHC, their natural targets, or high levels of interleukin 2. Other factors made by such cells that also contribute to killing and may synergize with LT to accelerate

Figure 3 Expression of LTa from the rat insulin promoter (RIP) induces a mononuclear infiltration around the islets of Langer-hans in the pancreas. (A) Normal islet of nontransgenic mouse. (B) Inflamed islet of RIP-LTct transgenic mouse.

the process include interferon y (ITNF6), TNFa, perforin and serine proteases. The ability of LT to induce DNA fragmentation by apoptosis, a characteristic of cytolytic but not antibody plus com-plement-mediated killing, further implicates it in cell-mediated killing. Through its cytotoxic activity, LT probably contributes to graft rejection and to manifestations of graft-versus-host reactions. LT kills virus-infected target cells more effectively than non-infected cells, in part because of its synergism with IFNy. This property suggests that a crucial biologic role for LT may include defense against viruses, particularly through eliminating virus-infected cells.

LTa may also contribute towards the pathogenesis of autoimmune diseases. The ability of LTa to synergize with IFNy and interleukin 1 in destroying (3 cells of the islets of Langerhans suggests a role in insulin-dependent diabetes mellitus (IDDM). Observations of induction of myelin swelling by LT, its cytotoxicity against oligodendrocytes and its production by cells of the central nervous system in vitro and in multiple sclerosis plaques, implicate it in demyelinating diseases. Its role as an inflammatory mediator also suggests its involvement in such diseases with their prominent mononuclear infiltrates. LTa production is associated with the ability of T cells to transfer experimental allergic encephalomyelitis, a murine model of an autoimmune demyelinat-ing disease. Suggestive evidence for the contribution of LT to autoimmune disease susceptibility in humans comes from genetic linkage studies that demonstrate an association between a polymorphic allele of LTa with increased risk of diabetes.

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