Langerhans cells protect from allergic contact dermatitis in mice by tolerizing CD8+ T cells and activating Foxp3+ regulatory T cells
Mercedes Gomez de Agüero, … , Dominique Kaiserlian, Bertrand Dubois
Mercedes Gomez de Agüero, … , Dominique Kaiserlian, Bertrand Dubois
Published April 23, 2012
Citation Information: J Clin Invest. 2012;122(5):1700-1711. https://doi.org/10.1172/JCI59725.
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Research Article

Langerhans cells protect from allergic contact dermatitis in mice by tolerizing CD8+ T cells and activating Foxp3+ regulatory T cells

Abstract

Allergic contact dermatitis is the most frequent occupational disease in industrialized countries. It is caused by CD8+ T cell–mediated contact hypersensitivity (CHS) reactions triggered at the site of contact by a variety of chemicals, also known as weak haptens, present in fragrances, dyes, metals, preservatives, and drugs. Despite the myriad of potentially allergenic substances that can penetrate the skin, sensitization is relatively rare and immune tolerance to the substance is often induced by as yet poorly understood mechanisms. Here we show, using the innocuous chemical 2,4-dinitrothiocyanobenzene (DNTB), that cutaneous immune tolerance in mice critically depends on epidermal Langerhans cells (LCs), which capture DNTB and migrate to lymph nodes for direct presentation to CD8+ T cells. Depletion and adoptive transfer experiments revealed that LCs conferred protection from development of CHS by a mechanism involving both anergy and deletion of allergen-specific CD8+ T cells and activation of a population of T cells identified as ICOS+CD4+Foxp3+ Tregs. Our findings highlight the critical role of LCs in tolerance induction in mice to the prototype innocuous hapten DNTB and suggest that strategies targeting LCs might be valuable for prevention of cutaneous allergy.

Authors

Mercedes Gomez de Agüero, Marc Vocanson, Fériel Hacini-Rachinel, Morgan Taillardet, Tim Sparwasser, Adrien Kissenpfennig, Bernard Malissen, Dominique Kaiserlian, Bertrand Dubois

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Figure 6

LCs renders hapten-specific CD8+ T cells hyporesponsive to subsequent skin sensitization.

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LCs renders hapten-specific CD8+ T cells hyporesponsive to subsequent sk...
(A) In vivo assay to study CD8+ T cell functions. Cd3ε–/– T cell–deficient mice were injected i.v. with 5 × 106 (B) or 1 × 106 (C and D) purified CD8+ T cells and were skin sensitized with DNFB 1 day (B) or 4 weeks later (C and D). Five days after sensitization, recipient mice were sacrificed, and the frequency of the DNP-specific IFN-γ–producing cells in cutaneous LNs was determined by ELISpot. (B) Functions of CD8+ T cells purified from cutaneous LNs of B6 mice 6 days after abdominal skin painting with vehicle (white bars), DNTB (black bars), or DNFB (gray bars). (C) CD8+ T cells were isolated from Lang-DTR donor mice that were injected or not with DT 3 days prior to DNTB painting. (D) CD8+ T cells from naive B6 mice were cultured in vitro with LCs (1 LC for 20 CD8+ T cells) isolated from the epidermis 4 hours after vehicle (white bar) or DNTB (black bar) painting, were sorted to high purity after 3 days to remove LCs, and were injected into Cd3ε–/– mice. Results are expressed as the mean value ± SD of IFN-γ SFCs for 3 individual mice and are representative of 2 (B) and 3 (C and D) independent experiments. *P < 0.05; ***P < 0.001.