CD8+ T Cell Profiles in Patients With Rheumatoid Arthritis and Their Relationship to Disease Activity

Abstract

Objective. CD8؉ T cells are abundant in rheumatoid arthritis (RA). However, their role in disease pathogenesis is poorly defined. This study was undertaken to investigate the relationship between disease activity and CD8؉ T cell phenotypes, production of cytokines, and production of cytotoxic molecules in the peripheral blood (PB) and synovial fluid (SF) of patients with RA.Methods. CD8؉ T cell phenotypes were determined in 96 patients with RA (44 with disease in remission, 34 with active disease, 18 with low disease activity) and in 64 sex-and age-matched healthy controls. Ten paired PB and SF samples from patients with active RA were analyzed. The expression of surface markers, cytokines, and proteolytic enzymes in CD8؉ T cells was evaluated using flow cytometry.Results. PB CD8؉ T cells from RA patients with active disease exhibited an effector (CD27؊CD62L؊) phenotype (P ‫؍‬ 0.005), with elevated expression of proinflammatory cytokines (tumor necrosis factor ␣ [TNF␣], interferon-␥ [IFN␥], interleukin-6 [IL-6], IL-17A) when compared to healthy controls. In a state of remission, the same phenotype observed in patients with active disease persisted, including a significant increase in the frequency of CD69 (P < 0.001), but lower cytokine production was observed. SF CD8؉ T cells from RA patients expressed more robust effector memory (CD27؉CD62L؊) and activated (CD69؉) profiles compared to the T cell subsets in paired PB samples.

Direct recognition of LPS drive TLR4 expressing CD8+ T cell activation in patients with rheumatoid arthritis

“…2). The results obtained are in accordance to the previous report wherein CD8 + T cells of active RA patients were shown to produce mediators of cytotoxicity including Granzyme B, Perforin, TNFα and IFNγ 28 . The study also reported that RA patients have a selective increase in the CD27 − CD62L − CD8 + effector subpopulation of CD8 + T cells.…”

“…The presence of different subpopulations of CD8 + T cells, their increased cytotoxic and pro-inflammatory behavior in RA has been reported previously 28 and in line with this report 28 , we as well identified cytolytic and activated CD8 + T cells in RA patients. These cells expressed significant levels of mRNA transcripts for cytolytic molecules like Granzyme B and Perforin as well as inflammatory mediators like TNFα and IFNγ (Fig.…”

“…The present study also suggests that TLR4 signals directly drive Tc1 development and T cell activation independent of TCR engagement. While the mechanism is still unclear and currently under investigation, this is in agreement with the previous findings that TLR agonists selectively stimulate IFNγ but not IL-4 production by human γδ T cells 19, 22, 28 . The TCR independent T cell activation directly by TLR4 explains that TLR ligands besides influencing the adaptive immune response through APC activation can also drive polyclonal activation and differentiation of antigen-specific CD8 + T cells which may impact on the infection-exacerbated inflammatory and autoimmune diseases like RA.…”

“…Recently Carvelheiro et al . described different CD8 + T cell subsets and their cytokine profile related to RA disease activity 28 . They showed that the CD8 + T cells in active RA patients have a cytotoxic behavior and secrete significant amounts of pro-inflammatory cytokines like TNFα.…”

Inhibitory Receptor Expression on T Cells as a Marker of Disease Activity and Target to Regulate Effector Cellular Responses in Rheumatoid Arthritis

“…CD8 + and CD4 + T cells in SF showed similar frequencies and a strong positive correlation with the frequencies in the paired PB samples (Supplementary Figure 4B and C and data not shown). Similar to previous reports (20), we observed that central and effector memory subsets were significantly increased while naïve and terminal effector subsets were significantly reduced within the CD8 + and the CD4 + T cells from SF in comparison to the paired PB (Supplementary Figure 4D and 4F). Interestingly, after 3 months of treatment rRA, but not nrRA, patients showed significantly increased frequencies of CD8 + and CD4 + T cells with terminal effector phenotype (Supplementary Figure 4E and 4G).…”