A shift towards a type I immune response in chronic atopic dermatitis favours an IL-15 dependent tissue resident memory cell niche

Background: Tissue resident memory (TRM) cells are of interest in chronic inflammatory skin diseases as they are believed to facilitate flares in the same anatomical area.IL-15 is an J o u r n a l P r e -p r o o f 2 essential growth factor for the survival of TRM in the skin compartment.A main source of IL-15 are tissue-resident cells.Objective: The purpose of this study was to explore the role of IL-15 in the chronification process of atopic dermatitis (AD).Methods: Primary human keratinocytes and fibroblasts were cultured and exposed to a range of stimuli in order to assess their IL-15 expression and production, which were measured by qPCR and ELISA, respectively.RNAseq and PCR were performed from lesional and nonlesional atopic dermatitis (AD) biopsies.Results: We tested a range of type I and type II response-associated cytokines and PAMPs on primary human fibroblasts and keratinocytes.The main inducer for IL-15 in keratinocytes proved to be IFN, while fibroblasts showed responsiveness to long-term exposure to IL-4.Transcriptomic analyses of AD skin biopsies confirmed that IL-15 was associated with a higher IFN signature and longer disease duration, and a significant correlation was observed between IL-15 and the TRM molecules CCR8 and CD69. Conclusion:The epidermal compartment responds to IFNs with IL-15 expression.Analysis of patient-derived skin biopsies highlights higher expression of IL-15 in the context of a Th1 shift known to occur in chronic AD.These data suggest that flares require prompt intervention to avoid consolidation of an IFN-driven tissue memory.