Thymic Stromal Lymphopoietin Is Required for Gastrointestinal Allergy but Not Oral Tolerance

Abstract

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. 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. 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. 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.