Intestinal dendritic cell licensing through TLR4 is required for oral tolerance in allergic contact dermatitis

Publication date: Available online 22 March 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Feriel Hacini-Rachinel, Mercedes Gomez de Agüero, Reem Kanjarawi, Ludovic Moro-Sibilot, Jean-Benoit Le Luduec, Claire Macari, Gilles Boschetti, Emilie Bardel, Philippe Langella, Bertrand Dubois, Dominique Kaiserlian
BackgroundInduction of oral tolerance to haptens is an efficient way to prevent allergic contact dermatitis (ACD) in mice. Toll-like receptor (TLRs)-mediated sensing of the microbiota contributes to gut homeostasis, yet whether it contributes to induction of oral tolerance has not been documented.ObjectiveWe examined whether oral tolerance to the contact sensitizer DNFB depends on microbiota/TLRs and evaluated the role of TLR4 on the tolerogenic function of intestinal dendritic cells (DCs).MethodsOral tolerance was induced by DNFB gavage in germ-free (GF) and several TLR-deficient mice. Tolerance was assessed by suppression of contact hypersensitivity and of hapten-specific IFNγ-producing effector T cells. The tolerogenic function of intestinal DCs was tested by adoptive transfer experiments, ex vivo hapten-presentation and Foxp3 regulatory T cell conversion.ResultsOral tolerance induced by DNFB gavage was impaired in GF mice and in TLR4-deficient mice. Bone marrow chimeras revealed that TLR4 expression on hematopoietic cells was necessary for oral tolerance induction. TLR4 appeared to be essential for the ability of intestinal dendritic cells from DNFB-fed mice to inhibit ACD upon adoptive transfer. Indeed, TLR4 conditioned the in vivo mobilization to mesenteric lymph nodes of intestinal migratory CD103⁺ DCs carrying oral DNFB, especially the CD103⁺CD11b⁺ DC subset expressing the vitamin A-converting enzyme RALDH⁺ and specialized in Foxp3⁺Treg conversion.ConclusionsOur data demonstrate that TLR4 conditions induction of oral tolerance to DNFB via licensing tolerogenic gut DCs. Oral biotherapy with TLR4 ligands might be usefull to potentiate oral tolerance to haptens and alleviate ACD in humans.

Teaser

The commensal flora and expression of TLR4 on hematopoietic cells are essential for oral tolerance and suppression of DNFB-induced contact hypersensitivity. TLR4 conditions the mobilization of tolerogenic intestinal CD103⁺CD11b⁺ DCs carrying the allergen to MLNs.


http://ift.tt/2mwTdlt