Differentiation of IL-26(+) T(H)17 intermediates into IL-17A producers via epithelial crosstalk in psoriasis

Interleukin (IL)-26 is a T(H)17 cytokine with known antimicrobial and pro-inflammatory functions. However, the precise role of IL-26 in the context of pathogenic T(H)17 responses is unknown. Here we identify a population of blood T(H)17 intermediates that produce high levels of IL-26 and differentiate into IL-17A-producing T(H)17 cells upon TGF-β1 exposure. By combining single cell RNA sequencing, TCR sequencing and spatial transcriptomics we show that this process occurs in psoriatic skin. In fact, IL-26+ T(H)17 intermediates infiltrating psoriatic skin induce TGF-β1 expression in basal keratinocytes and thereby promote their own differentiation into IL-17A-producing cells. Thus, our study identifies IL-26-producing cells as an early differentiation stage of T(H)17 cells that infiltrates psoriatic skin and controls its own maturation into IL17A-producing T(H)17 cells, via epithelial crosstalk involving paracrine production of TGF-β1.