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

Autoimmune diseases such as rheumatoid arthritis (RA) represent a significant source of worldwide morbidity and disability. Despite extensive research, the molecular mechanisms underlying the development of self-reactive T cells and the breach of tolerance remain elusive. Specifically, the intricate gene expression patterns and T cell receptors (TCRs) responsible for autoimmune diseases are still largely unknown. Mutation in the ZAP-70 gene (SKG, ZAC) that cause moderate attenuation of TCR signaling, can result in autoimmune manifestations akin to RA in mice. This study aims to characterize the gene expression profiles and TCR repertoires of distinct autoreactive T cell populations within the joints, lymph nodes, and spleens of arthritic ZAC mice at the single-cell level, comparing them with those of wild-type (WT) and non-arthritic ZAP-70 mutant mice (SKG). Our analysis revealed two distinct populations of Th17 cells (Th17 Il22 + and Th17 Tnfsf11 +) in ZAC mice, each exhibiting unique transcriptional signatures, tissue distributions, and TCR repertoires. Notably, Th17 Tnfsf11 + cells, active in pathogenic transcriptional programs, are uniquely localized in inflamed joints and absent in WT or SKG mice. Furthermore, their TCR repertoire shared features with WT Treg repertoires, suggesting that reduced TCR signaling enables T cells bearing self-reactive TCRs to evade negative selection, leading to a repertoire shift from Treg to Tconv. This repertoire shift not only enables self-reactive Tconv development but also depletes specific Treg reactivities. These findings provide a comprehensive understanding of Treg and Tconv transcriptomes and repertoires in ZAP-70 mutant mice, contributing to a mechanistic understanding of the break in tolerance in autoimmune diseases.