Multi-dimensional analysis identified rheumatoid arthritis-driving pathway in human T cell

Abstract

ObjectivesRheumatoid arthritis (RA) is an autoimmune disease accompanied by lymphocyte infiltration into joint synovium. While T cells are considered to be important for its pathogenesis, the features that are the most relevant to disease and how they change after treatment remain unclear. The aim of this study was to clarify the characteristics of T cells in RA, comprehensively.MethodsWe enrolled a total of 311 patients with RA and 73 healthy participants, and carefully classified them by disease state, constructed multiple cohorts and analysed clinical samples from them in a stepwise manner. We performed immunophenotyping with multiple evaluation axes, and two independent transcriptome analyses complementary to each other.ResultsWe identified that ‘effector memory-Tfh’ subset was specifically expanded in the peripheral blood (PB) of patients with RA in correlation with disease activity, and reverted after treatment. Besides, we revealed distinct features of T cells in synovial fluid (SF) that the expression of Tfh/Tph-related genes and pro-inflammatory cytokines and chemokines, including CXCL13, were significantly enriched, whereas these phenotype were Th1-like. Finally, we identified specific pathways, such as mTORC1, IL-2-stat5, E2F, cell cycle and interferon-related genes, that were significantly enriched in SF, in particular, as well as PB of untreated patients with RA, and notably, these features reverted after treatment.ConclusionOur multi-dimensional investigation identified disease relevant T-cell subsets and gene signatures deeply involved in pathogenesis of RA. These findings could aid in our understanding of essential roles of T cells in RA and will facilitate to development better diagnostic and therapeutic interventions.

Molecular Remission at T cell level in Patients with Rheumatoid Arthritis

“…As shown in previous reports, obviously T cells were involved in the development and chronicity of RA [7][8][9][10]. Compared with CD4 + T cells, evidence of a role for CD8 + T cells in RA are emerging [9].…”

“…Clonal expansion was observed for CD8+ T cells but not for CD4+ T cells in newly diagnosed patients with RA, indicating requirement of them for initial phase of RA [20]. However, RA risk alleles were preferentially expressed in CD4 + T cells, not CD8 + T cells [7,8], and proportion of only CD4 + T cell subpopulations were positively associated with disease activity [10], suggesting CD4 + T cells more deeply contribute to the activity state of RA than CD8 + T cells.…”

“…Recently, to investigate clarify the comprehensive characteristics of T cells in RA, we conducted multidimensional, immunophenotyping analysis according to developmental stage: CD4 + T cells were classi ed into four subsets (naïve (TN), stem cell memory (TSCM), central memory (TCM) and effector memory (TEM)), whereas CD8 + T cells were classi ed into ve stages (TN, TSCM, TCM, TEM and CD45RA-positive effector memory (TEMRA)). The study demonstrated that CD8 + TEMRA increased in patients with RA compared with HCs, and TEM-follicular helper (Tfh) cells and TEM-T helper 17(Th17) cells were correlated with disease activity, suggesting T cells in patients with remission may represent MR state of RA [10].…”

High serum IgA and proportion of activated Th17 and Treg predict efficacy of abatacept in patients with early, seropositive rheumatoid arthritis

“…Second, immune-phenotyping analysis was not conducted in all the patients, and usage of cryopreserved PBMCs may decrease the reliability of the methods [47]. Third, more than half of the patients with immune-phenotyping analysis were treated with concomitant methotrexate, which may skew immunephenotyping and cytokine pro les [2]. Fourth, our analysis did not check other T cell subpopulations, which are also players in the adaptive immunity and involved in the pathogenesis of RA, such as the the follicular helper T cells and peripheral T helper cells [48,49].…”

“…For complete activation, T lymphocytes, the essential immune cells involved in the pathogenesis of RA [2], require co-stimulatory signals from antigen-presenting cells via the interaction of CD28 on T cells with CD80/86 on antigen-presenting cells. Abatacept is a soluble fusion protein consisting of an extracellular domain from the human cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and a modi ed F c portion from the human immunoglobulin (Ig) G1 [1], which interferes with T cell activation by competing against CD28 via the CTLA4 domain [3].…”