Atopic dermatitis and skin disease
Langerhans cells are critical in epicutaneous sensitization with protein antigen via thymic stromal lymphopoietin receptor signaling

https://doi.org/10.1016/j.jaci.2012.01.063Get rights and content

Background

The clarification of cutaneous dendritic cell subset and the role of thymic stromal lymphopoietin (TSLP) signaling in epicutaneous sensitization with protein antigens, as in the development of atopic dermatitis, is a crucial issue.

Objectives

Because TSLP is highly expressed in the vicinity of Langerhans cells (LCs), we sought to clarify our hypothesis that LCs play an essential role in epicutaneous sensitization with protein antigens through TSLP signaling.

Methods

By using Langerin-diphtheria toxin receptor knock-in mice and human Langerin-diphtheria toxin A transgenic mice, we prepared mice deficient in LCs. We also prepared mice deficient in TSLP receptors in LCs by using TSLP receptor–deficient mice with bone marrow chimeric technique. We applied these mice to an ovalbumin (OVA)-induced epicutaneous sensitization model.

Results

Upon the epicutaneous application of OVA, conditional LC depletion attenuated the development of clinical manifestations as well as serum OVA-specific IgE increase, OVA-specific T-cell proliferation, and IL-4 mRNA expression in the draining lymph nodes. Consistently, even in the steady state, permanent LC depletion resulted in decreased serum IgE levels, suggesting that LCs mediate the TH2 local environment. In addition, mice deficient in TSLP receptors on LCs abrogated the induction of OVA-specific IgE levels upon epicutaneous OVA sensitization.

Conclusion

LCs initiate epicutaneous sensitization with protein antigens and induce TH2-type immune responses via TSLP signaling.

Section snippets

Animals and bone marrow chimera

C57BL6 (B6) and BALB/c mice were purchased from Japan SLC (Shizuoka, Japan). OT-II T-cell receptor transgenic mice were purchased from the Jackson Laboratory (Bar Harbor, Me). Langerin-diphtheria toxin subunit A (DTA) mice were generated by Dr Daniel Kaplan,19 and Langerin-enhanced green fluorescent protein (eGFP)-diphtheria toxin receptor (DTR) knock-in mice were kindly provided by Dr Bernard Mallissen (CIML, Institut National de la Santé et de la Recherche Médicale, Marseille, France).

TSLPR−/−

LC depletion impaired the development of OVA-induced allergic skin dermatitis model

To assess the role of LCs in epicutaneous sensitization with protein antigens and induction of IgE, we applied OVA to mice epicutaneously.22 In this model, we observed a rise in OVA-specific serum IgE and IgG1 levels, both of which are induced in a TH2-dependent manner, as well as the development of dermatitis characterized by the infiltration of CD3+ T cells, eosinophils, and neutrophils and local expression of mRNA for the cytokines IL-4, IL-5, and IFN-γ.22 These findings exhibited

Discussion

In this study, we have demonstrated that LCs are the essential cutaneous DC subset in the induction of IgE upon epicutaneous sensitization with protein antigens. We also found that TSLPR expression on LCs is enhanced upon protein antigen exposure to the skin and that LCs plays an important role in this process through TSLP-TSLPR signaling. In addition, we have demonstrated that TSLP stimulation causes LCs to express OX40L as shown previously in human studies and that BM-derived DCs induce TH2

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      LCs mediate the Th2 local environment (Fig. 2). Mice deficient in thymic stromal lymphopoietin (TSLP) receptors on LCs abrogated the induction of ovalbumin-specific IgE levels upon epicutaneous ovalbumin sensitization.58 Thus, LCs initiate epicutaneous sensitization with protein antigens and induce type 2 immune responses via TSLP signaling, suggesting that LCs play a mandatory role in extrinsic AD.

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    This work was supported in part by Grants-in-Aid for Scientific Research from the Ministries of Education, Culture, Sports, Science and Technology (to K.K.) and by a Grant-in-Aid from the Japan Society for the Promotion of Science Fellows (to S.N.). This work was also supported by a grant from the NIH (AR056632 to D.H.K.) and the American Skin Association. B.Z.I. was supported by a grant from the Dermatology Foundation.

    Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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