Highlights d Method for pooled knockin screens of large DNA sequences at targeted genomic loci d Rapid discovery of novel synthetic constructs to enhance primary human T cell fitness d PoKI-seq combines pooled knockins with single-cell RNA sequencing in vitro and in vivo d Novel chimeric TGF-bR2-41BB receptor hit promotes solid tumor clearance
The IL-17 cytokine family and the cognate receptors thereof have a unique role in organ-specific autoimmunity. Most studies have focused on the founding member of the IL-17 family, IL-17A, as the central mediator of diseases. Indeed, although pathogenic functions have been ascribed to IL-17A and IL-17F in the context of immune-mediated glomerular diseases, the specific functions of the other IL-17 family members in immunity and inflammatory kidney diseases is largely unknown. Here, we report that compared with healthy controls, patients with acute Anti-neutrophil cytoplasmatic antibody (ANCA)-associated crescentic glomerulonephritis (GN) had significantly elevated serum levels of IL-17C (but not IL-17A, F, or E). In mouse models of crescentic GN (nephrotoxic nephritis) and pristane-induced lupus nephritis, deficiency in IL-17C significantly ameliorated the course of GN in terms of renal tissue injury and kidney function. Deficiency of the unique IL-17C receptor IL-17 receptor E (IL-17RE) provided similar protection against crescentic GN. These protective effects associated with a reduced T17 response. Bone marrow transplantation experiments revealed that IL-17C is produced by tissue-resident cells, but not by lymphocytes. Finally, IL-17RE was highly expressed by CD4 T17 cells, and loss of this expression prevented the T17 responses and subsequent tissue injury in crescentic GN. Our findings indicate that IL-17C promotes T17 cell responses and immune-mediated kidney disease IL-17RE expressed on CD4 T17 cells. Targeting the IL-17C/IL-17RE pathway may present an intriguing therapeutic strategy for T17-induced autoimmune disorders.
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