Thymic stromal lymphopoietin is required for gastrointestinal allergy but not oral tolerance

Background & Aims Thymic stromal lymphopoietin (TSLP) is a cytokine produced by epithelial cells that acts on dendritic cells, mast cells, T cells, and B cells. TSLP is involved in the pathogenesis of allergic inflammation in the lung and skin, but data indicate a regulatory role in the gastrointestinal tract. We tested the functional role of TSLP in mouse models of gastrointestinal allergy and tolerance. Methods TSLP Receptor (TSLPR)^+/+ and TSLPR^-/- mice were sensitized and challenged with ovalbumin; models of allergic diarrhea or systemic anaphylaxis were studied. To induce oral tolerance, mice were fed with low-dose ovalbumin before they were immunized with it. Tolerance was measured from inhibition of ear swelling in a delayed-type hypersensitivity reaction. Results TSLPR^-/- mice were protected from the onset of allergic diarrhea; they did not develop mastocytosis in the jejunum and had reduced ovalbumin-immunoglobulin E in their serum, compared with TSLPR^+/+ mice. TSLPR^-/- mice also lost T helper cell (Th) 2-mediated inflammation in the jejunum. In contrast, sensitization and oral tolerance were not impaired in TSLPR^-/- mice. Transfer of wild-type, Th2-primed cells to TSLPR^-/- mice completely restored the development of allergic diarrhea. Antigen presentation assays showed that TSLPR on T cells, but not dendritic cells, was required to mediate the Th2 response. Conclusions TSLP is required for allergic inflammation but not primary sensitization or tolerance to food proteins in the gastrointestinal tract; it amplifies Th2 responses directly from CD4⁺ T cells.