Abstract
TNF-like ligand 1A (TL1A), which binds its cognate receptor DR3 and the decoy receptor DcR3, is an identified member of the TNF superfamily. TL1A exerts pleiotropic effects on cell proliferation, activation, and differentiation of immune cells, including helper T cells and regulatory T cells. TL1A and its two receptors expression is increased in both serum and inflamed tissues in autoimmune diseases such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and ankylosing spondylitis (AS). Polymorphisms of the TNFSF15 gene that encodes TL1A are associated with the pathogenesis of irritable bowel syndrome, leprosy, and autoimmune diseases, including IBD, AS, and primary biliary cirrhosis (PBC). In mice, blocking of TL1A-DR3 interaction by either antagonistic antibodies or deletion of the DR3 gene attenuates the severity of multiple autoimmune diseases, whereas sustained TL1A expression on T cells or dendritic cells induces IL-13-dependent small intestinal inflammation. This suggests that modulation of TL1A-DR3 interaction may be a potential therapeutic target in several autoimmune diseases, including IBD, RA, AS, and PBC.
Highlights
TNF-like ligand 1A (TL1A), which binds its cognate receptor DR3 and the decoy receptor DcR3, is an identified member of the TNF superfamily
Sustained TL1A expression on T cells or dendritic cells leads to an increase in the number of activated CD4+ T cells and memory CD4+ T cells, whereas sustained TL1A expression on dendritic cells does not stimulate conventional T cells in the absence of TCR stimulation in vivo, suggesting that TL1A may act as a costimulator for T cells to regulate inflammatory cytokines and cell proliferation [26, 27]
Treg cells derived from mice that constitutively express TL1A under the CD11 promoter attenuate the ability to suppress conventional T cells in vitro [26], whereas Treg cells derived from mice constitutively expressing TL1A under the CD2 promoter maintain their suppressive ability [27]. These results suggest that the effect of TL1A-DR3 interaction on T cells might be highly dependent on experimental conditions in vitro or the context of the immune response that is being modulated in vivo
Summary
TL1A, referred to as vascular endothelial growth inhibitor (VEGI)-251, is a member of the tumor necrosis factor superfamily (TNFSF) of ligands, which was identified by Migone et al in 2002 [1]. Human TL1A consists of 251 amino acids: 35 in the cytoplasmic domain, 24 in the transmembrane region, and 192 in the extracellular domain. TL1A expression is detected on human umbilical vein endothelial cells and synovial fibroblast-like cells and is upregulated by stimulation with proinflammatory cytokines such as TNF-α, IL-1, and PMA, a phorbol ester known to be a potent activator of protein kinase C [1, 4]. DR3, known as APO-3, TRAMP, LARD, and WSL-1, is a member of the tumor necrosis factor receptor superfamily (TNFRSF) with a typical death domain that consists of an approximately 60-amino-acid globular bundle of 6 conserved α helices found in the cytoplasmic region. Pappu et al showed that DR3 splicing variants are differentially expressed on T-cell subsets in mice [13]
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