The pathogenic role of stem cell-like memory T cells in rheumatoid arthritis

Abstract Background: Stem cell-like memory T cells (Tscm) are a subset of memory T cells that have the characteristics of stem cells. The role of Tscm cells in rheumatoid arthritis (RA) is not well characterized. Methods: After measuring percentages of CD4+ and CD8+ Tscm cells within the peripheral blood and synovial mononuclear cell populations in RA and health controls (HCs), we confirmed the stem cell nature of Tscm cells from RA patients. The association of Tscm cells with disease activity was also analyzed. Next, the pathogenicity of Tscm cells was examined in RA patients by assessing T cell activation markers and cytokine secretion after stimulation with IL-6 and anti-CD3/CD28 beads. Finally, the transcriptomes of Tscm cells from RA patients were compared with those from HCs. Results: The percentages of CD4+ and CD8+ Tscm cells among total T cells were significantly higher in RA patients than in HCs. Upon stimulation, Tscm cells from RA patients differentiated into daughter T cell subsets with self-renewal capacity. The percentage of CD4+ Tscm cells correlated with expression of RA disease activity markers. Tscm cells from RA patients were more easily activated by IL-6 and anti-CD3/CD28 beads than those from HCs. Transcriptome analysis revealed that Tscm cells from RA patients showed patterns distinct from those of HCs. Conclusion: The percentage of transcriptionally distinct and potentially pathogenic Tscm cells are higher in RA patients than in HCs; these cells may be a continuous source of pathogenic T cells, which perpetuate RA.