The biological role of the TNF super family ligand TL1A and its receptor DR3

Abstract

Members of the Tumor Necrosis Factor superfamily of cytokines are an important source of costimulatory signalling required for the proper activation of T cells. One such receptor-ligand pair is Death receptor 3 (DR3) and its ligand TNF-like ligand 1A (TL1A). Genetic variants in TL1A are associated with inflammatory bowel disease and TL1A-DR3 interactions are required for full pathology in murine models of asthma, multiple sclerosis and colitis, with DR3 on T cells thought to play a major role in promoting immunopathology. Tumor Necrosis Factor superfamily cytokines, including TL1A, are synthesised as type II transmembrane proteins, some of which are subsequently cleaved to yield a soluble form in the serum. We have investigated the biological function of transmembrane versus soluble TL1A in mice using a mutant that prevents cleavage of TL1A from the plasma membrane. Overexpression of either full length or membrane restricted TL1A promoted an IL-13 driven small intestinal pathology which appeared earlier in mice where soluble TL1A was present. We hypothesise that this may be due to cell-type specific effects of the different forms of TL1A. In these same mice we identified increased total IgA in the serum, and went on to demonstrate that DR3 deficient mice have a defect in IgA in response to immunisation and TL1A can promote IgA class switching in vivo. Lastly we assessed the role of DR3 in lupus-like murine models. Here we found lack of DR3 was protective for the development of kidney disease. Overall we have shown that different forms of TL1A can have differing functions and that TL1A is important for components of both the humoral and cellular immune response.

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ORCID for Aymen Al-Shamkhani: orcid.org/0000-0003-0727-4189

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