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

Significance Statement
CD4+ IL-17A–producing CD4+ T helper (TH17) 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+ TH17 cells. Disruption of the IL-17R signaling pathway in these cells potentiates TH17 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 TH17 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-TH17 treatment strategies.

Background
IL-17A–producing CD4+ 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., CD4+ T cell subsets, remains to be elucidated.

Methods
Crescentic GN (nephrotoxic nephritis) was induced in IL-17A, IFNγ, and Foxp3 triple-reporter mice for sorting of renal CD4+ 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 CD4+CD45RBhigh T cell transfer colitis model.

Results
We identified a specific expression of the IL-17 receptor A/C complex on CD4+ TH17 cells. Single-cell 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 CD4+ T cells and, most importantly, specifically in CD4+ 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 CD4+ 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.