IL-17 Receptor C Signaling Controls CD4+ TH17 Immune Responses and Tissue Injury in Immune-Mediated Kidney Diseases
Authors: Tilman Schmidt, Jonas Luebbe, Christoph Kilian, Jan-Hendrik Riedel, Sonja Hiekmann, Nariaki Asada, Pauline Ginsberg, Lennart Robben, Ning Song, Anna Kaffke, Anett Peters, Alina Borchers, Richard A. Flavell, Nicola Gagliani, Penelope Pelzcar, Samuel Huber, Tobias B. Huber, Jan-Eric Turner, Hans-Joachim Paust, Christian F. Krebs, Ulf Panzer
Journal: Journal of the American Society of Nephrology (2021)

Significance Statement CD4 + IL-17A–producing CD4 + T helper (T H 17) cells play a unique role in autoimmune and chronic inflammatory diseases of the kidney, skin, and gut. Their proinflammatory functions are mediated through the release of IL-17A and -F, which activate the IL-17 receptor A (IL-17RA) and IL-17RC signaling pathways in epithelial and endothelial cells. We report that the IL-17RA/IL-17RC complex is highly expressed in CD4 + T H 17 cells. Disruption of the IL-17R signaling pathway in these cells potentiates T H 17 cell pathogenicity and accelerates experimental crescentic GN. Comparable results were observed in experimental models of psoriasis and colitis. These findings indicate that IL-17 receptor signaling controls the T H 17 response via the IL-17RA/IL-17RC complex through a self-inhibitory loop in immune-mediated diseases and might provide new insights into the development of more efficient anti-T H 17 treatment strategies. Background IL-17A–producing CD4 + T helper (T H 17) 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. , CD4 + T cell subsets, remains to be elucidated. Methods Crescentic GN (nephrotoxic nephritis) was induced in IL-17A, IFN γ , and Foxp3 triple-reporter mice for sorting of renal CD4 + T cell subsets and subsequent single-cell RNA sequencing. Moreover, we generated T H 17 cell–specific IL-17RA and IL-17RC gene–deficient mice and studied the functional role of IL-17 signaling in T H 17 cells in crescentic GN, imiquimod-induced psoriasis, and in the CD4 + CD45RB high T cell transfer colitis model. Results We identified a specific expression of the IL-17 receptor A/C complex on CD4 + T H 17 cells. Single-cell RNA sequencing of T H 17 cells revealed the activation of the IL-17 receptor signaling pathway in experimental crescentic GN. Disruption of the IL-17RC signaling pathway in CD4 + T cells and, most importantly, specifically in CD4 + T H 17 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 CD4 + T H 17 cells and in the control of organ-specific autoimmunity and might provide new insights into the development of more efficient anti-T H 17 treatment strategies.