IL-23 maintains tissue resident memory Th17 cells in murine and psoriatic skin

Abstract

Abstract Tissue resident memory Th17 cells (TRM17) are the key cell type driving the chronic skin inflammation of psoriasis. Although IL-23 is strongly associated with autoimmunity and chronic inflammatory disorders including psoriasis, and anti-IL-23 biologic agents have remarkable efficacy in the treatment of psoriasis, the precise role of IL-23 in supporting IL-17-mediated skin inflammation remains unclear. In mice, we found that circulating memory T cells were dispensable for anamnestic protection from C. albicans skin infection, and TRM17 mediated protection from C. albicans reinfection required IL-23. Administration of anti-IL-23R antibody to dual Il17aCre Rosa26CAG-fl/fl-tdTomato Il17fThy1.1/Thy1.1 (17Fate) fate reporter mice following resolution of primary C. albicans infection resulted in a selective reduction in the number of CD69+CD103+TRM17 cells in skin compared with isotype controls. TRM17 proliferation was reduced and survival was unaffected. CD301b+ dermal dendritic cells (dDC) were an obligate source of IL-23 that supported TRM17 maintenance in skin after C. albicans challenge. These data demonstrate that locally produced IL-23 promotes in situ TRM17 proliferation to support their long term retention in skin. In normal human skin, we identified dermal cDC2 as the principal source of IL-23, although keratinocytes and CD4+ T cells were additional sources of IL-23 in psoriasis skin. Analysis of human psoriasis skin before and after clinical anti-IL-23 therapy revealed reduced TRM17 number and proliferation index, suggesting that targeted depletion of pathogenic TRM17 is the major mechanism by which anti-IL-23 therapy induces uniquely durable disease-free intervals in psoriasis patients.