Langerhans cells are critical in epicutaneous sensitization with protein antigen via thymic stromal lymphopoietin receptor signaling

Abstract

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.

Dermal dendritic cells, but not Langerhans cells, are critical in murine single epicutaneous sensitization

“…Based on surface markers, dDCs can be further divided into langerin + and langerin À dDCs (7)(8)(9). Using a repeated proteinpatch model, LCs were shown to be critical in EC sensitization and to induce Th2 responses via TSLP signalling (10). Our group also previously demonstrated that arsenic mobilizes LC migration and induces the Th1 response in repeated EC protein sensitization via CCL21 (11).…”

New insights in the pathogenesis of atopic dermatitis

“…TSLP activates dendritic cells (DC) to produce chemokines such as thymus-and activation-regulated chemokine/ chemokine (C-C motif) ligand (CCL)17 and macrophagederived chemokine/CCL22, which leads to infiltration of Th2 cells in AD lesions (19). In a recent AD mouse model, TSLP was shown to activate cutaneous group 2 innate lymphoid cells (ILCs; Figure 1) (20).…”

Second-Generation Langerhans Cells Originating from Epidermal Precursors Are Essential for CD8+ T Cell Priming

“…However, studies using transgenic mice, which enable in vivo ablation of LCs, suggested a more limited function for LCs. It was shown that LCs can prime CD4 + Th17 cells under inflammatory conditions, as well as Th2 responses via thymic stromal lymphopoietin signaling (3,4). LCs also can limit adaptive immune responses by stimulating the differentiation of T regulatory cells (5)(6)(7).…”