Study of TSLP signaling through dendritic cells in driving skin T cell responses
MEYER P. 1, GUIVARCH M. 1, MARSCHALL P. 1, VU MANH T. 2, HENER P. 1, ADA DA SILVA G. 1, SEGAUD J. 1, GERMAN FALCON B. 1, DALOD M. 2, LI M. 1
1 IGBMC - CNRS UMR 7104 - Inserm U 1258 - Université de Strasbourg, France, Illkirch, France; 2 Centre d’Immunologie Marseille-Luminy (CIML), CNRS UMR 7280 - INSERM U 1104 - Aix-Marseille Université UM2, Marseille, France
Objectives: Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects up to 20% of children and 3-5% of adults worldwide. AD typically presents an aberrant type 2 immune response, shown by skin infiltration of T helper 2 (Th2) cells, eosinophils and basophils, accompanied Tfh cell response and an elevation of blood immunoglobulin E levels. The keratinocyte-derived cytokine TSLP has been recognized to play a key role in AD pathogenesis, but how TSLP signals through its receptor (TSLPR) expressed on dendritic cells (DCs) to drive T cell response remain to be investigated.
Methods: We used a TSLP overexpression-induced AD model originally established in the lab. We employed DC-selective knock-out mouse lines and gene reporter mouse tools, combined with flow cytometry and single cell transcriptomic analyses, and DC-T cell coculture to investigate TSLP-driven T cell response.
Results: We showed TSLP-TSLPR signaling in DCs not only induces Th2 but also regulatory T cells (Treg). We found that TSLP-activated DCs upregulated their expression of the costimulatory molecule OX40L, thus took use of our newly generated OX40L knockout mice to characterize the implication of OX40L from DC in Th2/Treg responses, as well as OX40L-reporter mice to identify these DCs from surface marker expression to transcriptomic profiles.
Conclusions: Our results provide insights on how skin TSLP signals through DCs to drive different T cell responses.
Acknowledgement: We would like to acknowledge the funding supports from l’Agence Nationale de la Recherche (ANR-19-CE17-0017; ANR-19-CE17-0021; ANR-22-CE14-0023)