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 2

Both LCs and CD207– dDCs migrate to LNs upon induction of cutaneous tolerance.

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Both LCs and CD207– dDCs migrate to LNs upon induction of cutaneous tole...
To track DC migration from skin to draining LNs, Lang-EGFP mice (A–C), various types of BM chimeric mice (D), and B6 mice (E) were ear painted with either vehicle, DBP, or DNTB, followed by application of TRITC on the same site. At different time points after ear painting, CD11c+ cells were enriched from cervical LNs and the frequency of TRITC+ cells was determined by flow cytometry. (A) Representative dot plot of EGFP versus TRITC expression by LN DCs (gated as viable CD11c+ cells) at 48 hours. The numbers indicate the percentages of TRITC+EGFPhi (LCs and CD207+ dDCs) and TRITC+EGFP– (CD207– dDCs) cells among LN DCs. (B) Percentages of TRITC+EGFPhi and TRITC+EGFP– cells in a pool of 3 independent experiments (mean ± SD). (C) Frequency of TRITC+ cells among LN EGFPhi DCs in Lang-EGFP mice (mean ± SD) and (D) in various BM chimeric mice at 48 hours after painting. DC chimerism in both the epidermis and dermis is shown in Supplemental Figure 1, and results correspond to the mean of 2 independent experiments. (E) Representative profile of EGFP versus CD103 expression in skin-emigrated DCs (gated as viable CD11c+MHC-IIhiTRITC+ cells) at 24 hours and 72 hours after skin painting with DNTB showing the percentages of CD207– dDCs, CD207+CD103+ dDCs, and CD207–CD103– LCs (left panels). Absolute frequency of each TRITC+ DC subset among LN skin-derived CD11c+MHC-IIhi DCs (right panel).