IL-17 receptor c signaling controls CD4+TH17 immune responses and tissue injury in immune-mediated kidney diseases

Abstract

Background IL-17A producing CD41 T helper (TH17) cells play a critical role in autoimmune and chronic inflammatory diseases, such as crescentic GN. The proinflammatory effects of IL-17 are mediated by the activation of the IL-17RA/IL-17RC complex. Although the expression of these receptors on epithelial and endothelial cells is well characterized, the IL-17 receptor expression pattern and function on hematopoietic cells, e.g., CD41 T cell subsets, remains to be elucidated. Methods Crescentic GN (nephrotoxic nephritis) was induced in IL-17A, IFNg, and Foxp3 triple-reporter mice for sorting of renal CD41 T cell subsets and subsequent single-cell RNA sequencing. Moreover, we generated TH17 cell specific IL-17RA and IL-17RC gene deficient mice and studied the functional role of IL-17 signaling in TH17 cells in crescentic GN, imiquimod-induced psoriasis, and in the CD41CD45RBhigh T cell transfer colitis model. Results We identified a specific expression of the IL-17 receptor A/C complex on CD41 TH17 cells. Singlecell RNA sequencing of TH17 cells revealed the activation of the IL-17 receptor signaling pathway in experimental crescentic GN. Disruption of the IL-17RC signaling pathway in CD41 T cells and, most importantly, specifically in CD41 TH17 cells, potentiates the IL-17 cytokine response and results in an accelerated course of experimental crescentic GN. Comparable results were observed in experimental models of psoriasis and colitis. Conclusions Our findings indicate that IL-17 receptor C signaling has a previously unrecognized function in the regulation of CD41 TH17 cells and in the control of organ-specific autoimmunity and might provide new insights into the development of more efficient anti-TH17 treatment strategies.