Abstract
Interleukin (IL)-26 is a TH17 cytokine with known antimicrobial and pro-inflammatory functions and is highly expressed in tissues of TH17-mediated inflammatory diseases including psoriasis. However, the expression of IL-26 with respect to IL-17A and its precise function in the context of pathogenic TH17 responses are still unclear. In this study, we used flow cytometry-based fluorescent in situ hybridization of blood TH17 cells along with single-cell and spatial transcriptomics of psoriatic skin lesions to analyze the dynamic of the regulation of IL-26 expression in TH17 cells. We show that blood TH17 cells contain a large population of IL-26-producing cells that do not produce IL-17A. Unlike IL-17A-producing cells, these IL-26-producing cells develop at early stages of TH17 differentiation and do not require TGF-β. However, when exposed to TGF-β, IL-26-producing cells transition into IL-17 producers, a process also observed in psoriatic skin lesions, where TGF-β is highly expressed by basal keratinocytes in close vicinity to IL-26-producing T cells. T cell-derived IL-26 was able to induce TGF-β expression in keratinocytes themselves, suggesting a mechanism by which TH17 cells control IL-17A responses in tissues via the expression of IL-26. Thus, our study identifies IL-26-producing cells as an early differentiation stage of TH17 cells that can further differentiate into IL-17A producing cells upon tissues infiltration via a paracrine loop involving TGF-β.
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