Background/Purpose: Previous reports showed that both CD4 and CD8 T cells were related to the RA disease activity, such as Th17, follicular helper 2, and activated CD8 T cells. On the other hand, T cells can be divided according to developmental stages, and it is controversial whether T cell proceeds development in RA, partly because aging greatly influences T cell development. Recently, the least developed memory T cell subset, stem cell memory T (Tscm), was found among cells with naive phenotype, therefore, peripheral blood (PB) T cells can be divided into naive (Tn), Tscm, central memory (Tcm), and effector memory (Tem) in CD4, and these plus CD45RA+ effector memory (Temra) in CD8. Although human Tscm were reported in patients with bone marrow transplantation, it has not been studied in autoimmune diseases. The purpose of this study was to elucidate the T cell abnormality among each developmental stages including newly identified Tscm in RA patients.

Methods: PB samples from 56 untreated RA patients and 38 healthy controls (HC), and 14 synovial fluid (SF) samples with paired PB from same RA patients were collected. The proportion of each developmental stage and activating status was determined by flow cytometry. Tn, Tscm, Tcm, Tem, and Temra subset from PB of 6 RA and HC were sorted, and analyzed gene expression by microarray.

Results: PB T cells were greatly influenced by age and individual differences, however, the proportion of developed cells tended to increases in RA. Especially, the proportion of CD4 Tscm was significantly high in RA (p=0.02), and CD8 Tscm also tended to be high. In transcriptome analysis, most of subsets were clustered by developmental stage rather than disease, suggesting that influence of disease was not so big among same developmental stages (Fig 1). Remarkably, CD8 Tem and Temra were apparently different between RA and HC. Pathway/upstream analysis showed that this difference may be derived from cytokines such as VEGF, PDGF, and IL-6. In comparison of T cells in PB and SF, the proportion of developed and activated cells was high in SF (Fig 2). Interestingly, most of CCR7+CD45RO-cells in SF, which had been classified as naive, were actually Tscm. In addition, the proportion of activated CD4 and CD8 Tscm in SF were correlated with RA disease activity.

Conclusion: Although the PB T cell in RA had smaller differences with that of HC than expected, several cytokine signatures were found in CD8 Tem and Temra of RA. In SF, almost all T cells, including cells which has been considered naive, were memory cells. Activating status of Tscm in both CD4 and CD8, correlated with RA disease activity, indicating that these subsets participated in RA pathophysiology.