Th17 cells with a pathogenic signature in joints of ZAP-70 mutant arthritic mice harbor unique TCR repertoires that share features with WT Tregs

Mutations in the ZAP-70 gene that cause moderate attenuation of T cell receptor (TCR) signaling in mice can result in autoimmune manifestations. One explanation for this pathology is a shift in the regulatory-conventional (Treg-Tconv) T cell repertoire composition. To test this hypothesis, we characterized the single-cell gene expression profiles and TCR repertoires of Tconv and Treg CD4+ T cells of arthritic (ZAC), poised (SKG) ZAP-70 mutant, and wild-type (WT) mice. We identified a group of Th17 cells which exhibited a pathogenic signature and occurred exclusively in inflamed joints of ZAC mice. Such pathogenic signature was uniquely detected in CD4+ T cells obtained from inflamed joints of RA patients. Overall, the Tconv repertoires of ZAP-70 mutant mice were increasingly similar to the repertoires of WT Tregs, and this effect was most notable in the subset of pathogenic Th17 cells. Our results support a model where, upon moderate ZAP-70-mediated signal weakening, T cells that would normally develop into Tregs, instead develop into self-reactive Tconvs, resulting in a breakdown in self-tolerance and susceptibility to autoimmune arthritis.