Intestinal dendritic cell licensing through Toll-like receptor 4 is required for oral tolerance in allergic contact dermatitis.
Induction of oral tolerance to haptens is an efficient way to prevent allergic contact dermatitis (ACD) in mice. Toll-like receptor (TLR)-mediated sensing of the microbiota contributes to gut homeostasis, yet whether it contributes to induction of oral tolerance has not been documented.



We examined whether oral tolerance to the contact sensitizer 2,4-dinitro-fluorobenzene (DNFB) depends on microbiota/TLRs and evaluated the role of TLR4 on the tolerogenic function of intestinal dendritic cells (DCs).



Oral tolerance was induced by DNFB gavage in germ-free and mice deficient in several TLRs. Tolerance was assessed by means of suppression of contact hypersensitivity and hapten-specific IFN-γ-producing effector T cells. The tolerogenic function of intestinal DCs was tested by adoptive transfer experiments, ex vivo hapten presentation, and forkhead box p3 regulatory T-cell conversion.



Oral tolerance induced by DNFB gavage was impaired in germ-free mice and 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 on 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 retinaldehyde dehydrogenase and specialized in forkhead box p3-positive regulatory T-cell conversion.



Our data demonstrate that TLR4 conditions induction of oral tolerance to DNFB through licensing tolerogenic gut DCs. Oral biotherapy with TLR4 ligands might be useful to potentiate oral tolerance to haptens and alleviate ACD in human subjects.
Mucosal Immunity, Vaccination & Biotherapies Laboratory, INSERM U1111-CNRS UMR5308, Université Claude Bernard Lyon 1, Ecole Normale Superieure de Lyon, Lyon, France.
Feriel
F
Hacini-Rachinel
Mucosal Immunity, Vaccination & Biotherapies Laboratory, INSERM U1111-CNRS UMR5308, Université Claude Bernard Lyon 1, Ecole Normale Superieure de Lyon, Lyon, France.
Mercedes
M
Gomez de Agüero
Mucosal Immunity, Vaccination & Biotherapies Laboratory, INSERM U1111-CNRS UMR5308, Université Claude Bernard Lyon 1, Ecole Normale Superieure de Lyon, Lyon, France.
Reem
R
Kanjarawi
Mucosal Immunity, Vaccination & Biotherapies Laboratory, INSERM U1111-CNRS UMR5308, Université Claude Bernard Lyon 1, Ecole Normale Superieure de Lyon, Lyon, France.
Ludovic
L
Moro-Sibilot
Mucosal Immunity, Vaccination & Biotherapies Laboratory, INSERM U1111-CNRS UMR5308, Université Claude Bernard Lyon 1, Ecole Normale Superieure de Lyon, Lyon, France.
Jean-Benoit
JB
Le Luduec
Mucosal Immunity, Vaccination & Biotherapies Laboratory, INSERM U1111-CNRS UMR5308, Université Claude Bernard Lyon 1, Ecole Normale Superieure de Lyon, Lyon, France.
Claire
C
Macari
Mucosal Immunity, Vaccination & Biotherapies Laboratory, INSERM U1111-CNRS UMR5308, Université Claude Bernard Lyon 1, Ecole Normale Superieure de Lyon, Lyon, France.
Gilles
G
Boschetti
Mucosal Immunity, Vaccination & Biotherapies Laboratory, INSERM U1111-CNRS UMR5308, Université Claude Bernard Lyon 1, Ecole Normale Superieure de Lyon, Lyon, France.
Emilie
E
Bardel
INRA, UMR1319 Commensal and Probiotics-Host Interactions Laboratory, Micalis Institute, Jouy-en-Josas, France.
Philippe
P
Langella
Mucosal Immunity, Vaccination & Biotherapies Laboratory, INSERM U1111-CNRS UMR5308, Université Claude Bernard Lyon 1, Ecole Normale Superieure de Lyon, Lyon, France.
Bertrand
B
Dubois
Mucosal Immunity, Vaccination & Biotherapies Laboratory, INSERM U1111-CNRS UMR5308, Université Claude Bernard Lyon 1, Ecole Normale Superieure de Lyon, Lyon, France. Electronic address: dominique.kaiserlian@inserm.fr.
Dominique
D
Kaiserlian
D000818:Animals; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D017449:Dermatitis, Allergic Contact / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004139:Dinitrofluorobenzene / Q000633:toxicity; D000069196:Gastrointestinal Microbiome / Q000276:immunology*; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D007422:Intestines / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*
C000611649:IFNG protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D007371:Interferon-gamma; D004139:Dinitrofluorobenzene
Oral tolerance; Toll-like receptor 4; contact dermatitis; dendritic cells; microbiota