CD4 CD25high regulatory T cells are not impaired in patients with primary Sjögren's syndrome
Introduction
Primary Sjögren's syndrome (pSS) is an autoimmune disorder characterized by lymphocytic infiltration of the salivary and lacrimal glands leading to xerostomia and xerophthalmia. This syndrome, whose prevalence is estimated to be 0.2% to 0.5% in the general population, could be nearly as common as rheumatoid arthritis and is often complicated by extra-glandular manifestations, the most serious being non-Hodgkin's lymphoma [1], [2]. The pathogenesis of pSS is dominated by target-organ T cell infiltrates; destruction of the glandular epithelial cells, which are subjected to signals inducing their apoptosis; and polyclonal activation of B cells [3], [4].
A constitutive and high level of expression of the IL-2 receptor alpha chain (CD 25) defines a subset of naturally arising CD4 regulatory cells, the CD4 CD25high T cells. The CD4 CD25high T cells were first characterized in animals, as a population of suppressor T cells that maintain peripheral immune tolerance by inhibiting the activation and expansion of self-reactive T cells. In vitro suppression requires T cell receptor (TCR)-mediated activation of CD4 CD25high T cells and is mediated through a cell-contact mechanism, independent of cytokines [5], [6], [7]. Recently, Foxp3, a transcription factor, has been reported to be specifically expressed by this subset of T cells [8]. The expansion of Foxp3-expressing CD4 CD25high cells could be dependent on TGF-beta [9], [10]. Unfortunately, no cell-surface markers can absolutely discriminate between regulatory T cells and activated T cells: a consistent feature of proposed surface markers of these regulatory T cells, including CD25, cytotoxic T-lymphocyte antigen 4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR), is that they can all be acquired in CD4 CD25− responder T cells with cellular activation [11].
Very few studies have investigated the potential role of these cells in human autoimmune diseases. To date, to individualize regulatory CD4 CD25 T cells in the absence of specific phenotypic markers, one must consider only CD4 CD25 T cells with a high expression level of CD25 and ensure that these CD4 CD25high T cells exhibit a functional activity of suppression. With these restrictions, some studies tried to characterize human blood CD4 CD25high cells, which could represent 1–10% of CD4+ T cells in human peripheral blood [12], [13], [14], [15], [16]. The aim of the present study was to determine the number, function and repertoire of CD4 CD25high circulating cells in patients with pSS.
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Patients
Twenty-one patients with pSS as determined by the American–European consensus group criteria (four criteria, including positive results for anti-SSA/SSB antibodies or focus score ≥1; mean age 53.3±15.3 years; mean disease duration 11.5±6.8 years) were studied. Nine patients had extraglandular involvement of disease (presence or confirmed records of synovitis, myositis, vasculitis, or skin, neurological or renal involvement) and eight were treated with prednisone and/or methotrexate. Eight
Increased proportion of CD4 CD25high cells in pSS
Unaware of the possibility of an age bias, we first compared the population of CD4 CD25high cells in patients with pSS, in patients with lumbar back pain of mechanical origin and in healthy blood donors, who were markedly younger. The CD4 CD25high cell population was significantly increased in patients with pSS (8.5±11.5%) compared with blood donors (3.3±1.4%, P=0.007) (Table 1). Since healthy blood donors were younger, we investigated whether an age bias could explain these results. Indeed,
Discussion
This study demonstrated that the CD4 CD25high T cell population was unexpectedly increased in patients with pSS. The experimental data definitely show that we dealt with suppressive cells, since functional assays demonstrated that proliferation of CD4 CD25− responder cells were suppressed by 54–87%, when they were co-cultured with CD4 CD25 cells at a ratio of 1 to 1. The higher numbers of CD4 CD25high T cells in patients with pSS must be interpreted with caution, since CD4 CD25high regulatory T
Acknowledgements
We acknowledge Laurence Meyer and Beatrice Ducot (INSERM U292, Department of Biostatistics and Public Health, Bicêtre Hospital), for helpful statistical discussions.
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- 1
JEG was supported by The Institut National Pour la Santé et la Recherche Médicale (INSERM).
- 2
These authors participated equally in the work.