Dual function of Langerhans cells in skin TSLP-promoted TFH differentiation in mouse atopic dermatitis

Abstract

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.