Abstract
BackgroundRegulatory T cells (Tregs) are essential in the control of tolerance. Evidence implicates Tregs in human autoimmune conditions. Here we investigated their role in systemic sclerosis (SSc).Methods/Principal FindingsPatients were subdivided as having limited cutaneous SSc (lcSSc, n = 20) or diffuse cutaneous SSc (dcSSc, n = 48). Further subdivision was made between early dcSSc (n = 24) and late dcSSc (n = 24) based upon the duration of disease. 26 controls were studied for comparison. CD3+ cells were isolated using FACS and subsequently studied for the expression of CD4, CD8, CD25, FoxP3, CD127, CD62L, GITR, CD69 using flow cytometry. T cell suppression assays were performed using sorted CD4CD25highCD127- and CD4CD25lowCD127high and CD3+ cells. Suppressive function was correlated with CD69 surface expression and TGFβ secretion/expression. The frequency of CD4+CD25+ and CD25highFoxP3highCD127neg T cells was highly increased in all SSc subgroups. Although the expression of CD25 and GITR was comparable between groups, expression of CD62L and CD69 was dramatically lower in SSc patients, which correlated with a diminished suppressive function. Co-incubation of Tregs from healthy donors with plasma from SSc patients fully abrogated suppressive activity. Activation of Tregs from healthy donors or SSc patients with PHA significantly up regulated CD69 expression that could be inhibited by SSc plasma.Conclusions/SignificanceThese results indicate that soluble factors in SSc plasma inhibit Treg function specifically that is associated with altered Treg CD69 and TGFβ expression. These data suggest that a defective Treg function may underlie the immune dysfunction in systemic sclerosis.
Highlights
Over the past decade, there have been tremendous advances in our understanding of the basic processes that control immune tolerance
Further analysis focusing on CD25+bright and CD25+very bright cells revealed a similar expression of the markers FoxP3 and CD127 among all individuals, both on the levels of percentage positive cells (Figure 1c, d), as well on the mean fluorescence intensity (MFI, data not shown)
These data suggest that systemic sclerosis (SSc) patients have a markedly increased frequency of T regulatory cells, which is not related to an altered expression of markers characterizing Treg phenotype
Summary
There have been tremendous advances in our understanding of the basic processes that control immune tolerance. The identification of CD4+CD25+ regulatory T cells (Tregs) as a crucial component of self-tolerance has opened a major area of investigation and numerous studies have demonstrated the potent influence of Tregs in suppressing autoimmune disease, transplantation and graft-versus-host disease [1,2,3,4,5,6,7]. In the periphery of young mice not prone to autoimmune disease, Tregs constitute a stable 10% of CD4+ T cells. Mice genetically prone to autoimmune disease such as diabetes have markedly diminished circulating Tregs [9,10]. Evidence implicates Tregs in human autoimmune conditions. We investigated their role in systemic sclerosis (SSc)
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