The biological function of membrane versus soluble TL1A (CCR3P.205)

Abstract The Tumour Necrosis Factor Superfamily (TNFSF) are an important source of costimulatory signals required for activation of T cells. The TNFSF is composed of 29 receptors and 18 ligands; one such pair is Death receptor 3 (DR3) and TNF-like ligand 1A (TL1A). Signalling via DR3 costimulates lymphocytes and polymorphysims in TL1A and DR3 have been associated with Crohn's Disease. In mice, signalling via DR3 has been shown to be required for maximal pathology in models of asthma and lupus and transgenic constitutive expression of TL1A results in an IL-13 and IL-17a driven intestinal pathology. Several TNFSF ligands, including TL1A, can be expressed on the membrane and cleaved to yield a soluble product. Some cytokines, such as TNF are active in soluble form whereas others, such as FasL, are not. The biological roles of these distinct forms of TL1A in vivo are not known. To investigate the biological function of membrane vs. soluble TL1A we used retrotransgenic technology to express cleavable vs. membrane bound TL1A throughout the murine hematopoietic system. Membrane restricted TL1A promoted a strong inflammatory pathology in both the ileum and lung. Full length TL1A expression yielded little membrane TL1A. These mice failed to develop pathology despite a greater than physiological level of TL1A in the serum. This work demonstrated that membrane restricted TL1A is a more potent ligand for DR3. We have generated membrane-restricted TL1A transgenic mice to investigate this further.