IL-17 Receptor C Signaling Controls CD4⁺ T_H17 Immune Responses and Tissue Injury in Immune-Mediated Kidney Diseases

Background: IL-17A-producing CD4⁺ T helper (T_H17) 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 T_H17 cell-specific IL-17RA and IL-17RC gene-deficient mice and studied the functional role of IL-17 signaling in T_H17 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_H17 cells. Single-cell RNA sequencing of T_H17 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_H17 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_H17 cells and in the control of organ-specific autoimmunity and might provide new insights into the development of more efficient anti-T_H17 treatment strategies.