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Gastrointestinal Dendritic Cells Promote Th2 Skewing via OX40L¹

Division of Pediatric Allergy and Immunology, and the Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029

Mice can be sensitized to food proteins by oral administration with the adjuvant cholera toxin (CT), such that they undergo anaphylaxis when rechallenged with the sensitizing allergen. In contrast, feeding of Ags alone leads to oral tolerance. Our aim was to define the mechanisms by which gastrointestinal dendritic cells (DCs) participate in the deviation of tolerance to allergic sensitization in the gut in response to CT. BALB/c mice were fed with CT or PBS. The impact of CT on DC subsets in the mesenteric lymph node (MLN) was assessed by flow cytometry. Ag presentation assays were performed with DCs isolated from the MLN of PBS- or CT-fed mice, using OVA-specific CD4⁺ T cells as responder cells. Gene expression in MLN DCs was determined by real-time PCR, and neutralizing Abs were used to test the function of OX40 ligand (OX40L) in Th2 skewing. Oral administration of CT induced an increase in the total CD11c⁺ population in the MLN. CT induced a selective increase in migration of the CD11c⁺CD11b^–CD8^– DC subset and the maturation of all DC subsets. Maturation of DCs in vivo enhanced T cell proliferation and cytokine secretion. Oral CT induced up-regulation of Jagged-2 and OX40L by MLN DCs. Neutralizing anti-OX40L Abs completely abrogated the CT-induced Th2 cytokine response. We show that oral CT induces selective DC migration, maturation, and T cell priming activity in the MLN. Th2 skewing is mediated by OX40L, and we speculate that this molecule may be an important inducer of allergic sensitization to food allergens.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by National Institutes of Health Grant DK0715676 (to M.C.B.). A.B.B. was supported by a fellowship from the Crohn’s and Colitis Foundation of America.

² Address correspondence and reprint requests to Dr. M. Cecilia Berin, Pediatric Allergy and Immunology, Box 1198, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029. E-mail address: cecilia.berin{at}mssm.edu

³ Abbreviations used in this paper: DC, dendritic cell; CT, cholera toxin; DN, double negative; MLN, mesenteric lymph node; OX40L, OX40 ligand; PP, Peyer’s patch; pLN, peripheral lymph node.