The Presence of Cytokine‐Suppressive CD4⁺CD25⁺ T Cells in the Peripheral Blood and Synovial Fluid of Patients with Rheumatoid Arthritis

Abstract

CD4þ CD25 þ T cells have been shown to play a regulatory or suppressive role in the immune response and are possibly relevant to the pathogenesis of autoimmune diseases. In the present study, we attempted to investigate the levels of CD4 þ CD25 þ T cells in the peripheral blood (PB) and synovial fluid (SF) of patients with rheumatoid arthritis (RA) and the effects of CD4 þ CD25þ T cells on the in vitro cytokine production by stimulated SF mononuclear cells (SFMC). The results showed that RA patients had similar frequencies of CD4 þ CD25 þ T cells in PB, expressed as a percentages of the lymphocyte population, as did healthy subjects (mean AE SD: 10.52 AE 5.87% versus 11.11 AE 4.58%., respectively). But in contrast to PB, the SF of RA patients contained significantly higher levels of CD4 þ CD25 þ T cells (17.77 AE 7.92% versus 10.52 AE 5.87%, respectively. P < 0.001). When cocultured in vitro with SFMC, CD4 þ CD25þ T cells purified from either PB or SF were found to exert a considerable suppressive effect on the production of cytokines including TNF-a, IFN-g and interleukin-10 (IL-10). The percentages of inhibition of each cytokines ranged from 41.8 to 98.4% (mean, 80.0%) for TNF-a, 42.8 to 98.9% (mean, 83.2%) for IFN-g and 59.3 to 96.6% (mean, 80.0%) for IL-10. Because both pro-inflammatory and anti-inflammatory cytokines were suppressed by CD4 þ CD25 þ T cells, whether CD4 þ CD25 þ T cells might play a beneficial role in the suppression of sustained inflammation in rheumatoid synovium remains to be elucidated.

A Dual Action of Rheumatoid Arthritis Synovial Fibroblast IL-15 Expression on the Equilibrium between CD4+CD25+ Regulatory T Cells and CD4+CD25− Responder T Cells

“…It is widely accepted that the frequency and the suppressor potency of CD4 ϩ CD25ϩ Treg found in the synovial fluid of RA patients are significantly elevated when compared with peripheral blood (25,(53)(54)(55)(56), and our results are consistent with previous observations. A question that has been asked by several investigators (25,53,54) is why an active joint inflammation persists in RA despite the presence of elevated frequencies of CD4 ϩ CD25 ϩ T cells with an enhanced suppressive capacity.…”

Intravenous Immunoglobulin Therapy Affects T Regulatory Cells by Increasing Their Suppressive Function

“…In agreement with these findings, the interaction of CD4 ϩ CD25 ϩ Treg cells with activated monocytes in the joint of RA patients might lead to diminished suppressive activity of Treg cells in vivo, thus contributing to the chronic inflammation in RA (25). With these results in mind, and the fact that the blockade of TNF-␣ by therapy with anti-TNF has proven to be beneficial by inhibiting inflammation and preventing joint damage in RA patients, one may assume that this clinical effect might be mediated in part by a restoration of the defective function of CD4 ϩ CD25 ϩ Treg cells in patients with active RA.…”

Role of regulatory T cells in rheumatoid arthritis: facts and hypothesis

“…47 Autoimmun Since phenotypic characterization does not allow a definite conclusion as to whether expanded CD4 + CD25 high T cells in the SF are actually Treg, the most convincing evidence is undoubtedly provided by in vitro functional studies. Suppressive activity of CD4 + CD25 high T cells in the SF has been confirmed in some studies by coculture with autologous effector T cells [33][34][35][36][37][38][39]. In contrast, some authors have demonstrated a reduced suppressive activity of Treg cells in PB from RA patients, that can be restored by adequate pharmacological therapy, as discussed in detail below (see Table 2).…”