Differentiation of IL-26 T17 intermediates into IL-17A producers via epithelial crosstalk in psoriasis.

Interleukin (IL)-26 is a T17 cytokine with known antimicrobial and pro-inflammatory functions. However, the precise role of IL-26 in the context of pathogenic T17 responses is unknown. Here we identify a population of blood T17 intermediates that produce high levels of IL-26 and differentiate into IL-17A-producing T17 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+ T17 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 T17 cells that infiltrates psoriatic skin and controls its own maturation into IL17A-producing T17 cells, via epithelial crosstalk involving paracrine production of TGF-β1.