Diminished γδ T Cells during allergic skin inflammation is mediated by IL-4 signaling in keratinocytes

Abstract

Abstract Atopic dermatitis results in profound changes in the function of the skin that include diminished barrier function and altered production of antimicrobial peptides. Dendritic epidermal γδ T cells (DETC) are a subset of γδ T cells that play an important role in the wound repair and inflammation process. Our previous work identified a loss of DETC in Stat6VT mice and in MC903 induced skin inflammation mouse model that was dependent on IL-4. However, the mechanisms through which IL-4 mediates this loss of DETCs are still not clear. In this study, we show that IL-4Rα germline knockout mice (Il4ra−/−) have an increased DETC population in skin that correlates with a higher rate of wound closure and increased EDC gene and fibronectin 1 expression. In Il4ra−/− mice, MC903 induced loss of DETCs was alleviated. Bone marrow chimeras of Il4ra−/− and WT bone marrow into Il4ra−/− mice retained the increased DETCs in the skin of Il4ra−/− host mice. Importantly, IL-15 secretion from skin keratinocytes was decreased dramatically in the MC903 induced skin inflammation model and injection of IL-15 rescued the loss of DETCs. Furthermore, conditional knock out of IL-4Rα from Keratinocytes of Il4ra fl/fl K14cre mice also showed an increase of this DETC populations in skin, increased IL-15 expression and less skin inflammation. Together, these results identify an IL-4-dependent circuit that regulates DETCs in the skin by repressing IL-15 expression in keratinocytes. This provides further insights into the ability of IL-4 to promote the development of atopic lesions and impair wound healing. Supported by grants from NIH (R01AI095282)