Autoimmune rheumatologic diseases
We have previously identified two pathogenic CD4 subsets in both Teff (CPLs) and Treg (iaTreg) compartments that are HLA-DR+, antigen experienced, pro-inflammatory, correlating with disease activity and sharing TCR sequence oligoclonality with JIA synovial T cells. Despite being two functionally distinct T cell subsets, their phenotype and association with clinical fate suggests that these subsets may originate from a common precursor. To elucidate the common pathogenic gene drivers, we decided to perform next-generation RNA sequencing on sorted CPLs/iaTregs and their conventional Teff/Treg counterparts in both circulation and synovium. Comparative DEG analysis indicate transcriptomic convergence between circulatory CPLs/iaTreg and divergence from conventional effector/regulatory pools. Circulatory CPLs/iaTregs exhibit (a) common pathway dysregulation in T cell signalling, (b) restriction in TCR oligoclonality and (c) common transcription factor drivers (SPL1 and E2F1), suggesting a common antigenic selection pressure. Comparing healthy/JIA circulatory and paired synovium reveals a gradual transcriptomic convergence between Teff/CPLs, Treg/iaTreg and CPLs/iaTreg across the spatial/disease states. This is paralleled by an antigenic convergence in shared TCR clonotypes in CPLs/iaTreg across the same conditions. Synovium CPLs/iaTreg reveal 7 common dysregulated pathways; MHC II antigen presentation, T cell costimulation, IFNg pathway, apoptosis, viral response, bacteria response and chemotaxis. Overall the data indicate immune-phenotypic convergence between CPLs/iaTregs, that is strengthen across disease/spatial states. These findings underscore a potential mechanistic role of the inflammatory microenvironment in shaping two functionally dichotomic populations, relevant to disease pathogenies and progression.