CD25brightCD4+ regulatory T cells are enriched in inflamed joints of patients with chronic rheumatic disease - PubMed (original) (raw)

Comparative Study

doi: 10.1186/ar1192. Epub 2004 Jun 7.

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Comparative Study

CD25brightCD4+ regulatory T cells are enriched in inflamed joints of patients with chronic rheumatic disease

Duojia Cao et al. Arthritis Res Ther. 2004.

Abstract

CD25+CD4+ regulatory T cells participate in the regulation of immune responses. We recently demonstrated the presence of CD25brightCD4+ regulatory T cells with a capacity to control T cell proliferation in the joints of patients with rheumatoid arthritis. Here, we investigate a possible accumulation of these regulatory T cells in the inflamed joint of different rheumatic diseases including rheumatoid arthritis. The studies are also extended to analyze whether cytokine production can be suppressed by the regulatory T cells. Synovial fluid and peripheral blood samples were obtained during relapse from 36 patients with spondyloarthropathies, 21 adults with juvenile idiopathic arthritis and 135 patients with rheumatoid arthritis, and the frequency of CD25brightCD4+ T cells was determined. Of 192 patients, 182 demonstrated a higher frequency of CD25brightCD4+ T cells in synovial fluid than in peripheral blood. In comparison with healthy subjects, the patients had significantly fewer CD25brightCD4+ T cells in peripheral blood. For functional studies, synovial fluid cells from eight patients were sorted by flow cytometry, and the suppressive capacity of the CD25brightCD4+ T cells was determined in in vitro cocultures. The CD25brightCD4+ T cells suppressed the production of both type 1 and 2 cytokines including interleukin-17, as well as proliferation, independently of diagnosis. Thus, irrespective of the inflammatory joint disease investigated, CD25brightCD4+ T cells were reduced in peripheral blood and enriched in the joint, suggesting an active recruitment of regulatory T cells to the affected joint. Their capacity to suppress both proliferation and cytokine secretion might contribute to a dampening of local inflammatory processes.

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Figures

Figure 1

Figure 1

CD25brightCD4+ T cells are enriched in the joint of patients with rheumatic diseases and are decreased in peripheral blood. (a) Representative fluorescence-activated cell sorting plots of paired peripheral blood (PB) mononuclear cells and synovial fluid (SF) mononuclear cells from one patient with psoriatic arthritis (PsA). Numbers within the gates represent the percentage of CD25brightCD4+ T cells of all CD4+ T cells. (b) Frequency of CD25brightCD4+ T cells in synovial fluid of patients with PsA, spondyloarthopathies (SpA), juvenile idiopathic arthritis (JIA) and rheumatoid arthritis (RA). Each triangle represents one individual. (c) The frequencies of CD25brightCD4+ T cells in peripheral blood were compared between healthy subjects and rheumatic patients. Significant differences between patient group and healthy subjects are indicated with asterisks: *** P < 0.0001; ** P = 0.001; * P = 0.02. Note that the scale is different from that in (b). (d) Relative increase of CD25brightCD4+ T cells in synovial fluid in comparison with that in peripheral blood (fold increase) analyzed in all patients from whom paired synovial fluid and peripheral blood samples had been obtained. na, not applicable.

Figure 2

Figure 2

CD25brightCD4+ T cell population persists over time. (a) Eight patients with psoriatic arthritis (PsA), (b) four patients with spondyloarthopathies (SpA) and (c) eight patients with juvenile idiopathic arthritis (JIA) were followed longitudinally, and the frequency of synovial CD25brightCD4+ T cells was measured at each relapse from which synovial fluid was obtained. Open symbols depict patients who had two relapses during the study period; filled symbols depict patients who had three or more relapses. Time point zero corresponds to the first time point at which synovial fluid was analyzed for the frequency of CD25brightCD4+ T cells. From one patient with PsA and one with SpA, samples from both knees were obtained; arrows pointing left, left knee; arrows pointing right, right knee.

Figure 3

Figure 3

The frequency of CD25brightCD4+ T cells of patients with rheumatoid arthritis is not associated with clinical parameters. Peripheral blood (PB, left column) and synovial fluid (SF, right column) were analyzed for the correlation with (a) disease duration, (b) the presence or absence of rheumatoid factor (RF), (c) the presence or absence of erosions, (d) the level of C-reactive protein and (e) intra-articular cortisone treatment. In (a), (b) and (c) each symbol represents one patient; that is, mean values of CD25brightCD4+ T cells from the different visits. In (d) and (e) each symbol represents a single visit; the number of symbols in each diagram is presented in brackets.

Figure 4

Figure 4

Sorting gates and disease characteristics for patients included in the functional studies. Each row represents one patient. The sorting gates for isolation of CD25bright (25bright) and CD25- (R) T cells are indicated in the fluorescence-activated cell sorting plots, which are gated on CD3+ cells. Under treatment only so-called disease-modifying anti-rheumatic drugs (DMARDs) are presented. All patients also received non-steroidal anti-inflammatory drugs.

Figure 5

Figure 5

CD25brightCD4+ T cells suppressed both proliferation and cytokine secretion of synovial responder cells. CD25brightCD4+ T cells and CD25- CD4+ T cells (RSF) from two patients with psoriatic arthritis (PsA), two with spondyloarthopathies (SpA), two with juvenile idiopathic arthritis (JIA), and two with rheumatoid arthritis (RA) were sorted by flow cytometry. Increasing numbers of CD25brightCD4+ T cells were added to a fixed number of autologous RSF in coculture. Proliferation was measured after 6 days of culture with anti-CD3 stimulation (filled symbols). Culture supernatants were analyzed for cytokine content (open symbols). A response of 100% equals a proliferation/cytokine secretion of CD4+ RSF on their own. IFN, interferon; IL, interleukin; TNF, tumor necrosis factor.

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