Keratinocyte-derived CCL20 orchestrates epidermal localization of IL-17-producing γδ T cells and ILCs to mediate psoriasis-like skin inflammation

Abstract

Abstract CCR6 is important for imiquimod (IMQ)-induced psoriatic dermatitis in mice, which depends on motile CCR6+ γδ T cells that produce IL-17 and IL-22. CCR6 ligands include CCL20 and β-defensins. We used new strains of Ccl20 tdTomato knock-in mice, Ccl20fl/flmice, and Ccr6fl/fl GFP knock-in mice to determine sites of production and action of CCL20 and its role in the localization of γδ T cells and ILCs during imiquimod (IMQ)-induced inflammation. IMQ treatment of Ccl20+/tdT mice led to expression of Ccl20 in keratinocytes (KCs), including in the infundibulum and isthmus of the hair follicles. Ccl20−/− mice showed reduced inflammation and expression of Il17 and Il22 in the treated skin. Deletion of Ccl20 specifically in the KCs by treating Ccl20fl/flK14-CreERT mice with tamoxifen before applying IMQ significantly decreased the accumulation of IL-17-producing gd T cells and ILCs in the epidermis. Depleting KC-derived CCL20 at day 4 when inflammation was well established also reduced the number of epidermal γδ T cells and ILCs. In both cases the percent of IL-17-producing γδ T cells and ILCs did not change, demonstrating that migration to the epidermis and the ability to produce IL-17 are regulated independently. Multi-photon microscopy of IMQ-treated Ccr6+/gfp and Ccr6gfp/gfp(CCR6-deficient) micerevealed a CCR6-independent step whereby dermal CCR6+ cells accumulate at the hair follicles, followed by a CCR6-dependent step whereby the cells move into the superficial epidermis.