Antigen-Driven Pd-1(+)Tox(+)Bhlhe40(+) And Pd-1(+)Tox(+)Eomes(+) T Lymphocytes Regulate Juvenile Idiopathic Arthritis In Situ

T lymphocytes accumulate in inflamed tissues of patients with chronic inflammatory diseases (CIDs) and express pro-inflammatory cytokines upon re-stimulation in vitro. Further, a significant genetic linkage to MHC genes suggests that T lymphocytes play an important role in the pathogenesis of CIDs including juvenile idiopathic arthritis (JIA). However, the functions of T lymphocytes in established disease remain elusive. Here we dissect the transcriptional and the clonal heterogeneity of synovial T lymphocytes in JIA patients by single-cell RNA sequencing combined with T cell receptor profiling on the same cells. We identify clonally expanded subpopulations of T lymphocytes expressing genes reflecting recent activation by antigen in situ. A PD-1(+)TOX(+)EOMES(+) population of CD4(+) T lymphocytes expressed immune regulatory genes and chemoattractant genes for myeloid cells. A PD-1(+)TOX(+)BHLHE40(+) population of CD4(+), and a mirror population of CD8(+) T lymphocytes expressed genes driving inflammation, and genes supporting B lymphocyte activation in situ. This analysis points out that multiple types of T lymphocytes have to be targeted for therapeutic regeneration of tolerance in arthritis.