Dual function of Langerhans cells in skin TSLP-promoted TFH differentiation in mouse atopic dermatitis - 05/05/21
Abstract |
Background |
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.
Objectives |
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).
Methods |
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.
Results |
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.
Conclusions |
Together, these studies revealed a dual functionality of LCs in TSLP-promoted TFH and TH2 differentiation in AD pathogenesis.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Atopic dermatitis, TSLP, dendritic cells, Langerhans cells, TFH, TH2, allergen sensitization, mouse
Abbreviations used : AD, BAL, cDC1, cDC2, CT, D0, DC, DEG, DT, DTR, EDLN, GC, GFP, GFPneg (GFPpos), huLang, LangDEP, LC, LMP, LN, migDC, Neg_MC (Pos_MC), Neg_NT (Pos_NT), Neg_OVA (Pos_OVA), NT, OVA, OX40L, PD-1, TFH, TS, TSLPover, WT
Plan
| For this study, M.L. received funding support from l’Agence Nationale de la Recherche (ANR-17-CE14-0025; ANR-19-CE17-0017; ANR-19-CE17-0021), Fondation Recherche Medicale (Equipes-FRM 2018), and the first joint programme of the Freiburg Institute for Advanced Studies and the University of Strasbourg Institute for Advanced Study. The study was also supported by the grant ANR-10-LABX-0030-INRT, a French State fund managed by the Agence Nationale de la Recherche under the frame program Investissements d’Avenir ANR-10-IDEX-0002-02; the Centre National de la Recherche Scientifique; the Institut National de la Santé et de la Recherche Médicale, and the Université de Strasbourg. P.M. was supported by PhD fellowship from Region Alsace. R.W. and W.Y. were supported by PhD fellowships from the Association pour la Recherche à l’Institut de Génétique et de Biologie Moléculaire et Cellulaire. J.S. was supported by a PhD fellowship from Equipes-FRM 2018. |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 147 - N° 5
P. 1778-1794 - mai 2021 Retour au numéro
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