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.
View: Text | PDF
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

×

Figure 4

In vivo depletion of CD207+ DCs abrogates skin tolerance to DNTB and allows for priming of cytotoxic CD8+ T cells and CHS responses.

Options: View larger image (or click on image) Download as PowerPoint
In vivo depletion of CD207+ DCs abrogates skin tolerance to DNTB and all...
(A) Lang-DTR mice injected (black bars) or not (white bars) with DT at day –3 were tolerized with DNTB at day 0 or left untreated, and were sensitized with DNFB at day +7. The frequency of hapten-specific IFN-γ SFCs in LNs was determined by ELISpot in individual mice and is expressed as mean ± SD SFCs per 106 total LN cells. (B–D) Lang-DTR mice injected with DT at day –3 or day –15 were painted at day 0 with DNTB. On day +5, the frequency of hapten-specific IFN-γ–producing cells in LNs was determined (mean ± SD) (B). In vivo hapten-specific cytotoxic activity was calculated after injection of DNP-loaded target cells (mean ± SD) (C), and the ear-swelling response was determined 24 hours after ear challenge with DNTB (D). Each symbol corresponds to an individual mouse, and horizontal bars indicate the mean. Results correspond to 1 representative experiment out of 3, with 3 mice per group in each (A and C) and to pooled data from 2 (B, day –15; D) to 4 (B, day –3) independent experiments. Statistical analysis was performed using (A and B) the Kruskal-Wallis test with Dunn’s post-test and (C and D) the Mann-Whitney test. *P < 0.05; **P < 0.01. Data are shown as mean ± SD.