Abstract
Abstract The TNF-family cytokine TL1A costimulates T cells through its receptor DR3 and is required for diverse autoimmune disease models, but its role in innate lymphocyte biology has not been explored. Transgenic mice chronically expressing TL1A have increased activated T cells and develop small intestinal pathology characterized by high levels of IL-13, muscular and goblet cell hyperplasia, and infiltration with immune cells, all of which depend on DR3. Genetically eliminating T cells reduces T cell hyperactivation and gut infiltration with lymphocytes but not IL-13 production or mucosal hyperplasia. These data suggest that TL1A can induce another cell type to produce IL-13 and induce gastrointestinal pathology. Using a DsRED reporter mouse for IL-13, we find that the major IL-13 producing cells in TL1A transgenic mice lack T and B cell lineage markers and are phenotypically similar to ’type 2’ innate lymphocytes (ILC2) which expand and produce IL-13 in response to IL-25, IL-33 or parasitic infection. TL1A directly promotes IL-13 production by ILC2 ex-vivo. However, DR3 deficient mice mount a vigorous response to the intestinal nematode Nippostrongylus brasiliensis, and IL-13 producing innate lymphocytes can be expanded by IL-25 in the absence of DR3. Thus, TL1A can directly induce IL-13 production by innate lymphocytes through mechanisms distinct from parasitic infection. TL1A may be an attractive target for immunotherapy of diverse diseases associated with this cytokine.
Published Version
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