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 5

Epidermal LCs can transfer tolerance to DNTB.

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Epidermal LCs can transfer tolerance to DNTB. (A) Assessment of LC funct...
(A) Assessment of LC function by adoptive transfer. Ear epithelial sheets were prepared 4 hours after vehicle or DNTB painting and used to enrich for LCs by centrifugation over an OptiPrep gradient (low-density fraction). Naive B6 mice were transferred s.c. with 2.5 × 104 enriched LCs and were immunized 6 days later by s.c. injection of 105 DNBS-loaded BMDCs. The effect of LC transfer was determined by measuring the following: (B and F) the ear swelling that developed 24 hours after DNFB challenge (mean μm ± SD of 6 individual mice), (C and D) the capacity of CD8+ T cells isolated from LN 5 days after immunization to proliferate and to produce IFN-γ in vitro after stimulation with DNBS-loaded APCs (mean ± SD of triplicate wells), and (E and G) the frequency of DNP-specific IFN-γ–producing CD8+ T cells in LNs (mean SFCs per 106 CD8+ T cells ± SD of pooled mice, using 3–4 serial dilutions performed in duplicate). (B–D) Comparisons of the suppressive effect of LC transfer versus direct DNTB painting. (E) Lang-DTR mice, injected or not with DT 3 days before DNTB or vehicle ear painting, were used to prepare LCs (low-density fraction) or DETCs (high-density fraction) using an OptiPrep gradient (Supplemental Figure 5). (F and G) Comparison of the suppressive potential of LCs from B6, β2m–/– (F), and H2-Aβ1–/– (G) donor mice. *P < 0.05; **P < 0.01; ***P < 0.001.