Identification of disease-specific TCRs maintaining pathogenic T helper cell responses in postinfectious Lyme Arthritis

Antibiotic-refractory Lyme arthritis (ARLA) is defined by persistent arthritis after sufficient antibiotic treatment of acute Lyme arthritis and is seen in approximately 10% of patients with Lyme arthritis. Although some clinical and genetic risk markers for ARLA have been elucidated, whether chronic inflammation is sustained by persistent Borrelial antigens or triggered by autoantigens is not elucidated yet. Here, we show an oligoclonal expansion of peripheral T helper (TPH) cells in synovial fluid (SF) of pediatric ARLA patients. By in-depth bioinformatics analysis we identify a group of T cell receptors (TCRs) in this cell population shared between ARLA patients with a HLA-DRB1 11 background. By delineating surrogate markers for this convergent T cell response, we can show that these TCRs are specific for ARLA patients with HLA-DRB1 11 background compared to different autoimmune and infectious causes of arthritis and that those markers persist throughout disease course. Furthermore, combined single cell transcriptome and paired TCRa/b sequencing links the ARLA specific surrogate markers to cells with an inflammatory transcriptional program driven by TCR signaling - revealing possible therapeutic targets. Concluding, this study reveals an HLA-DRB1 restricted convergent TPH cell response in the joints of pediatric ARLA patients - suggesting a common persisting antigen as causative agent.