180 : The TNF family member TL1A: A key player in type 2 immunity in both adaptive and innate lymphocytes

Abstract

The TNF-family cytokine TL1A costimulates T cells through its receptor DR3. TL1A polymorphisms and increased TL1A expression has been linked to Rheumatoid Arthritis and Inflammatory Bowel Disease. TL1A-DR3 interactions are required for diverse mouse models of autoimmune disease. The effects of TL1A on T cell differentiation and its role in innate lymphocyte biology has not been explored. During T cell activation, we have found that TL1A costimulation specifically promotes production of the allergy-promoting cytokine IL-9 through a mechanism dependent on IL-2 and STAT5 signaling, and TL1A promotes pathology in mouse models of asthma and ocular inflammation. Transgenic mice chronically expressing TL1A spontaneously develop small intestinal pathology characterized by high levels of IL-13, muscular and goblet cell hyperplasia, and infiltration with immune cells. These histological changes are dependent on IL-13 but not T cells or commensal flora. 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 promote allergic and anti-parasitic responses in mice. ILC2 express surface DR3 and produce IL-13 in response to TL1A ex vivo. However, ILC2 can be expanded normally in DR3 deficient mice by IL-25 or IL-33, or Nippostrongylus brasiliensis, and DR3 deficient mice clear Nippostrongylus normally from the intestine. TL1A can thus induce IL-13 production by innate lymphocytes through mechanisms distinct from parasitic infection. Taken together, these data demonstrate that TL1A coordinately enhances type 2 immunity in both innate and adaptive lymphocytes and may be a good target for therapy in allergic diseases.