Cleavage of TL1A Differentially Regulates Its Effects on Innate and Adaptive Immune Cells.

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J Immunol. 2018 Jan 15. pii: ji1700891. doi: 10.4049/jimmunol.1700891. [Epub ahead of print]

Cleavage of TL1A Differentially Regulates Its Effects on Innate and Adaptive Immune Cells.

JR Ferdinand;AC Richard;F Meylan;A Al-Shamkhani;RM Siegel

Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892. Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom. University of Cambridge, Cambridge CB2 0XY; Department of Medicine, University of Cambridge, Cambridge CB2 0QQ.

Service type: Knock-in mice


TNF superfamily cytokines play major roles in the regulation of adaptive and innate immunity. The TNF superfamily cytokine TL1A (TNFSF15), through its cognate receptor DR3 (TNFRSF25), promotes T cell immunity to pathogens and directly costimulates group 2 and 3 innate lymphoid cells. Polymorphisms in the TNFSF15 gene are associated with the risk for various human diseases, including inflammatory bowel disease. Like other cytokines in the TNF superfamily, TL1A is synthesized as a type II transmembrane protein and cleaved from the plasma membrane by metalloproteinases. Membrane cleavage has been shown to alter or abrogate certain activities of other TNF family cytokines; however, the functional capabilities of membrane-bound and soluble forms TL1A are not known. Constitutive expression of TL1A in transgenic mice results in expansion of activated T cells and promotes intestinal hyperplasia and inflammation through stimulation of group 2 innate lymphoid cells. Through the generation of membrane-restricted TL1A-transgenic mice, we demonstrate that membrane TL1A promotes expression of inflammatory cytokines in the lung, dependent upon DR3 expression on T cells. Soluble TL1A alone was unable to produce this phenotype but was still able to induce intestinal type 2 inflammation independently of T cells. These data suggest differential roles for membrane and soluble TL1A on adaptive and innate immune cells and have implications for the consequences of blocking these two forms of TL1A.

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