Characterization of Effector Memory CD8+ T Cells in the Synovial Fluid of Rheumatoid Arthritis

Abstract

Little is known about the cellular characteristics of CD8(+) T cells in rheumatoid arthritis (RA). We addressed this by investigating whether the frequency of the CD8(+) T cell subsets and their phenotypic characteristics are altered in the peripheral blood and synovial fluid (SF) from patients with RA. In this study, CD8(+) T cells, mainly CD45RA(-) effector memory (EM) CD8(+) T cells, were increased significantly in the SF, but not in the peripheral blood from RA patients, compared with healthy controls. The synovial EM CD8(+) T cells were activated phenotypes with high levels of CD80, CD86, and PD-1, and had a proliferating signature in vivo upon Ki-67 staining, whereas the Fas-positive cells were prone to apoptosis. In addition, EM CD8(+) T cells in the SF were less cytotoxic, as they expressed less perforin and granzyme B. In particular, the proportions of synovial fluid mononuclear cells that were CCR4(+)CD8(+) T cells and IL-4-producing CD8(+) T cells (i.e., Tc2 cells) were significantly higher than those in peripheral blood mononuclear cells of patients with RA and healthy controls. In addition, the number of IL-10-producing CD8(+) suppressor T (Ts) cells increased significantly in the SF of RA patients. Especially, CD8(+) T cells were inversely correlated with disease activity. These findings strongly suggest that EM CD8(+) T cells in the SF are increased, likely because of inflammation, and they may be involved in modulating inflammation, thereby affecting the development and progression of RA.

T cells out of control—impaired immune regulation in the inflamed joint

“…Although little is known about the role of CD8 + T cells in joint pathology, high levels of these cells are present in synovial fluid, mainly with an effector memory phenotype, and produce marked amounts of proinflammatory cytokines, such as tumour necrosis factor (TNF) and IFN-γ. 6,20 Furthermore, in patients with JIA high levels of synovial fluid CD8 + T cells are correlated with a more progressive course of disease than is observed in patients with lower levels of these cells. 21 Specific T cell skewing in inflamed joints Notably, in the peripheral blood of patients with RA, the level of demethylation of Ifnγ and Il-17a is the same Key points ■ The study of immune regulation at the site of inflammation is required to improve our understanding of autoimmune pathology ■ At the site of autoimmune inflammation, proinflammatory mediators interfere with T-cell regulation and may induce T-cell plasticity ■ Regulatory T (T REG ) cells are less functional, or might even become pathogenic, in an autoimmune inflammatory environment, which should be kept in mind when developing T REG -cell-based therapies ■ Resistance of effector T cells to suppression markedly contributes to the disturbed immune balance in the inflamed joints of patients with arthritis ■ In autoimmune inflammation, a perpetuating loop exists in which antigen presenting cells (APCs) instruct T-cell differentiation and function, and effector T cells promote and shape the infiltration and differentiation of APCs as in healthy controls.…”

Immune regulation of multiple sclerosis by CD8+ T cells

“…CD8+ T cells from the lamina propria of patients with inflammatory bowel disease (IBD) lack regulatory activity otherwise present in healthy donors [15]. Synovial fluids of rheumatoid arthritis patients are enriched in suppressor CD8+ T cells [16]. Regulatory CD8+ T cell biology is more complex than appreciated earlier due to the heterogeneity in the phenotype of cells, as characterized by the surface markers.…”

Heterogeneity in the Differentiation and Function of CD8+ T Cells

“…Treg cells with preferential tropism for the gastrointestinal tract can be detected. These cells prevent graft versus host disease (GvHD) by inhibition of MHC class I-restricted T-cell responses and the suppressive T-cell population can be expanded by co-administration of rapamycin and IL-2/anti-IL-2 antibody complexes (Robb et al 2012 (Cho et al 2012) and human Tc17 cells predominantly belong to memory subsets (Kondo et al 2009), suggesting that at least in humans both subpopulations are able to establish memory cells. In a mouse tumor model, transferred Tc9 cells acquired a Tc1 memory phenotype, indicating that memory formation was associated with the transition into Tc1 cells (Lu et al 2014).…”