Dual function of Langerhans cells in skin TSLP-promoted T(FH) differentiation in mouse atopic dermatitis.

Atopic dermatitis (AD) is among the most common chronic inflammatory skin diseases, usually occurring early in life, and often preceding other atopic diseases such as asthma. TH2 has been believed to play a crucial role in cellular and humoral response in AD, but accumulating evidence has shown that follicular helper T cell (TFH), a critical player in humoral immunity, is associated with disease severity and plays an important role in AD pathogenesis. This study aimed at investigating how TFHs are generated during the pathogenesis of AD, particularly what is the role of keratinocyte-derived cytokine TSLP and Langerhans cells (LCs). Two experimental AD mouse models were employed: (1) triggered by the overproduction of TSLP through topical application of MC903, and (2) induced by epicutaneous allergen ovalbumin (OVA) sensitization. This study demonstrated that the development of TFHs and germinal center (GC) response were crucially dependent on TSLP in both the MC903 model and the OVA sensitization model. Moreover, we found that LCs promoted TFH differentiation and GC response in the MC903 model, and the depletion of Langerin+ dendritic cells (DCs) or selective depletion of LCs diminished the TFH/GC response. By contrast, in the model with OVA sensitization, LCs inhibited TFH/GC response and suppressed TH2 skin inflammation and the subsequent asthma. Transcriptomic analysis of Langerin+ and Langerin- migratory DCs revealed that Langerin+ DCs became activated in the MC903 model, whereas these cells remained inactivated in OVA sensitization model. Together, these studies revealed a dual functionality of LCs in TSLP-promoted TFH and TH2 differentiation in AD pathogenesis.

Marschall P ，Wei R ，Segaud J ，Yao W ，Hener P ，German BF ，Meyer P ，Hugel C ，Ada Da Silva G ，Braun R ，Kaplan DH ，Li M ... -  《-》

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

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. 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. 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. 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 T(H)2 local environment. In addition, mice deficient in TSLP receptors on LCs abrogated the induction of OVA-specific IgE levels upon epicutaneous OVA sensitization. LCs initiate epicutaneous sensitization with protein antigens and induce T(H)2-type immune responses via TSLP signaling.

Nakajima S ，Igyártó BZ ，Honda T ，Egawa G ，Otsuka A ，Hara-Chikuma M ，Watanabe N ，Ziegler SF ，Tomura M ，Inaba K ，Miyachi Y ，Kaplan DH ，Kabashima K ... -  《-》

TSLP produced by keratinocytes promotes allergen sensitization through skin and thereby triggers atopic march in mice.

Leyva-Castillo JM ，Hener P ，Jiang H ，Li M ... -  《-》

Thymic stromal lymphopoietin signaling in CD4(+) T cells is required for TH2 memory.

Thymic stromal lymphopoietin (TSLP) is a key factor in the development of allergic asthma. Numbers of TH2 memory cells gradually increase in allergic patients with the progression of disease and persist in the lungs during remission, although the mechanism is not clear. We sought to define the role of TSLP in TH2 memory cell generation and maintenance in vivo. Adoptive transfer of wild-type and thymic stromal lymphopoietin receptor (TSLPR)-deficient ovalbumin-specific CD4(+) T cells before TH2 sensitization was used to define T cell-specific TSLP effects. Atopic dermatitis and increased serum TSLP concentrations were induced by topical application of the vitamin D3 analog MC903. Memory cells in peripheral blood were monitored weekly with flow cytometry. Memory recall was tested after intranasal ovalbumin challenge. TSLP signaling in CD4(+) T cells is required for the generation/maintenance of memory cells after in vivo priming. TSLPR-deficient CD4(+) T cells have no defects in proliferation but do not survive 1 week after sensitization, and increased TSLP expression during sensitization significantly increased the frequency of memory cells. Although in vitro-differentiated TSLPR-deficient TH2 cells develop into memory cells with equal efficiency to wild-type cells, the recall response to airway antigen challenge is impaired. Moreover, after antigen challenge of mice with established TH2 memory, TSLP signaling in CD4(+) T cells significantly affects memory cell generation/maintenance from secondary effector cells. TSLP signaling in CD4(+) T cells is required for not only TH2 memory cell formation in vivo but also the recall response of the memory cells to local antigen challenge.

Wang Q ，Du J ，Zhu J ，Yang X ，Zhou B ... -  《-》

A population of dermal Langerin(+) dendritic cells promote the inflammation in mouse model of atopic dermatitis.

Cutaneous dendritic cells (DCs) have been implicated in the pathogenesis of atopic dermatitis (AD). However, the specific role of different subsets of DCs has not been well defined. This study aimed to investigate the contributions of Langerhans cells (LCs), resident dermal Langerin+ DCs (r-Langerin+ dDCs), and newly infiltrated inflammatory dermal Langerin+ DCs (i-Langerin+ dDCs) in an AD mouse model induced by the topical application of MC903. The result showed that depletion of i-Langerin+ dDCs in DTR mice after multiple diphtheria toxin (DT) injection significantly reduced thymic stromal lymphopoietin (TSLP) production in lesions and skin inflammation alleviation. However, depletion of LCs or r-Langerin+ dDCs didn't resulted in significant changes in skin inflammation of DTA or single DT injection-treated DTR mice compared with the wild-type (WT) mice. DT-treated DTR-WT chimeric mice with the depletion of bone marrow (BM)-derived i-Langerin+ dDCs resulted in markedly decreased skin inflammation than controls, while PBS-treated chimeric mice (DTR-WT) with only the depletion of r-Langerin+ dDCs showed inflammation comparable to that in WT mice. Furthermore, TSLP contributed to the upregulation of Langerin expression in BM-derived DCs and promoted the maturation of Langerin+ DCs. In summary, the present study demonstrated that the newly infiltrated inflammatory dermal Langerin+ DCs were essential for AD development and local TSLP production, and TSLP further promoted the production of BM-derived i-Langerin+ dDCs, which might maintain AD inflammation.

Xiao C ，Zhu Z ，Zhang C ，Gao J ，Luo Y ，Fang H ，Qiao H ，Li W ，Wang G ，Fu M ... -  《-》