Pathogenic Th17 cells in arthritogenic mice share T cell receptor features with Wild-type Tregs

Abstract

AbstractMutations in the ZAP-70 gene that cause moderate attenuation of T cell receptor (TCR) signaling in mice, can result in autoimmune manifestations akin to rheumatoid arthritis (RA). Here, we characterized the single-cell gene expression profiles and TCR repertoires of conventional (Tconv) and regulatory (Treg) CD4+T cells of arthritic (ZAC), poised (SKG) ZAP-70 mutant, and wild-type (WT) mice. We identified two Th17 cell subtypes in the joints of ZAC mice that were characterized by distinct transcriptional profiles and TCR repertoires, one of which exhibited a pathogenic signature and occurred exclusively in inflamed joints. Such a pathogenic signature was also uniquely detected in CD4+T cells obtained from inflamed joints of human RA patients. The TCR repertoire of pathogenic Th17 cells showed signs of increased intra-repertoire similarity (convergence) and was skewed toward the WT Treg rather than the WT Tconv repertoire. In addition, the overall similarity between the Treg and Tconv repertoires was severely reduced in arthritic mice. 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.