The 5G4.6 monoclonal antibody reacts with the TNF family member TL1A, also known as TNFSF15. TL1A is expressed on activated T cells, dendritic cells, monocytes and endothelial cells. TL1A expression has been shown to be induced by pro-inflammatory stimuli such as TNFα and IL-1α. In contrast to the TNFα receptors, which are expressed on essentially all cells, the receptor for TL1A, DR3 (TNFRSF25), is primarily expressed on T cells, NK cells, and NKT cells, thereby limiting the effects of TL1A. TL1A-DR3 interactions are thought to promote effector T cell proliferation at the site of inflammation and in draining lymph nodes. Blockade of TL1A-DR3 interactions strikingly reduces pathology in several animal models in which autoreactive T cells play a role. TL1A has been linked to inflammatory bowel disease. The 5G4.2 antibody has been shown to block TL1A binding to DR3 and reduce disease severity in mouse models of colitis.

INVIVOMAB ANTI-MOUSE TL1A (TNFSF15) (CLONE: 5G4.6)

Richard, A. C., et al. (2015). “The TNF-family ligand TL1A and its receptor DR3 promote T cell-mediated allergic immunopathology by enhancing differentiation and pathogenicity of IL-9-producing T cells.” J Immunol 194(8): 3567-3582. PubMed

The TNF family cytokine TL1A (Tnfsf15) costimulates T cells and type 2 innate lymphocytes (ILC2) through its receptor DR3 (Tnfrsf25). DR3-deficient mice have reduced T cell accumulation at the site of inflammation and reduced ILC2-dependent immune responses in a number of models of autoimmune and allergic diseases. In allergic lung disease models, immunopathology and local Th2 and ILC2 accumulation is reduced in DR3-deficient mice despite normal systemic priming of Th2 responses and generation of T cells secreting IL-13 and IL-4, prompting the question of whether TL1A promotes the development of other T cell subsets that secrete cytokines to drive allergic disease. In this study, we find that TL1A potently promotes generation of murine T cells producing IL-9 (Th9) by signaling through DR3 in a cell-intrinsic manner. TL1A enhances Th9 differentiation through an IL-2 and STAT5-dependent mechanism, unlike the TNF-family member OX40, which promotes Th9 through IL-4 and STAT6. Th9 differentiated in the presence of TL1A are more pathogenic, and endogenous TL1A signaling through DR3 on T cells is required for maximal pathology and IL-9 production in allergic lung inflammation. Taken together, these data identify TL1A-DR3 interactions as a novel pathway that promotes Th9 differentiation and pathogenicity. TL1A may be a potential therapeutic target in diseases dependent on IL-9.

Meylan, F., et al. (2011). “The TNF-family cytokine TL1A drives IL-13-dependent small intestinal inflammation.” Mucosal Immunol 4(2): 172-185. PubMed

The tumor necrosis factor (TNF)-family cytokine TL1A (TNFSF15) costimulates T cells through its receptor DR3 (TNFRSF25) and is required for autoimmune pathology driven by diverse T-cell subsets. TL1A has been linked to human inflammatory bowel disease (IBD), but its pathogenic role is not known. We generated transgenic mice that constitutively express TL1A in T cells or dendritic cells. These mice spontaneously develop IL-13-dependent inflammatory small bowel pathology that strikingly resembles the intestinal response to nematode infections. These changes were dependent on the presence of a polyclonal T-cell receptor (TCR) repertoire, suggesting that they are driven by components in the intestinal flora. Forkhead box P3 (FoxP3)-positive regulatory T cells (Tregs) were present in increased numbers despite the fact that TL1A suppresses the generation of inducible Tregs. Finally, blocking TL1A-DR3 interactions abrogates 2,4,6 trinitrobenzenesulfonic acid (TNBS) colitis, indicating that these interactions influence other causes of intestinal inflammation as well. These results establish a novel link between TL1A and interleukin 13 (IL-13) responses that results in small intestinal inflammation, and also establish that TL1A-DR3 interactions are necessary and sufficient for T cell-dependent IBD.