COMPARTMENTALIZATION, PERSISTENCE AND CONSERVED SHARED MOTIFS OF DOMINANT (REGULATORY) T CELL CLONES IN AUTOIMMUNE INFLAMMATION

Abstract

Introduction. In autoimmune diseases, inflammation is often limited to specific target tissues, but within tissues, multiple sites can be affected. Important outstanding questions are whether affected sites are infiltrated with the same (pathogenic) T-cell clones, whether these clones persist over time and whether they share specific motifs. Methods. In Juvenile Idiopathic Arthritis it is possible to analyze large number of cells derived from the inflamed joints. Here, we performed T cell receptor (TCR) sequencing to study local (hyper)expansion T(reg)-cells and the existence of an TCR immune fingerprint based on shared motifs with a newly developed algorithm. Samples were taken from different joints affected at the same time, and joints that were affected multiple times during the relapsing remitting course of the disease. Results. We observed a strong overlap between dominant T-cell clones, especially Treg, in inflamed joints affected at the same time. Some of the most dominant clones could also be detected in circulation. Dominant Treg and Teff cell clones were found to persist over time and to expand during relapses, even following full remission of the disease. Finally, despite having little overlap between patients for the exact TCR sequence, we found several shared immune fingerprints, based on sequence motifs, especially in the Treg. Conclusions. These data suggest that in autoimmune disease there is (dominant) auto-antigen driven expansion of both Teff and Treg clones that are highly persistent and (re)circulating. Therefore, these dominant clones can be interesting therapeutic targets. Furthermore, we demonstrate that TCR motif analyses maygive insights in disease-specific TCR patterns.