BACKGROUND: Regulatory 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 FINDINGS: Patients 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 CD4CD25(high)CD127(-) and 
CD4CD25(low)CD127(high) and CD3(+) cells. Suppressive function was correlated 
with CD69 surface expression and TGFbeta secretion/expression. The frequency of 
CD4(+)CD25(+) and CD25(high)FoxP3(high)CD127(neg) 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/SIGNIFICANCE: These results indicate that soluble factors in SSc 
plasma inhibit Treg function specifically that is associated with altered Treg 
CD69 and TGFbeta expression. These data suggest that a defective Treg function 
may underlie the immune dysfunction in systemic sclerosis.