Increased Frequency and Compromised Function of T Regulatory Cells in Systemic Sclerosis (SSc) Is Related to a Diminished CD69 and TGFβ Expression

• Published in: PloS one 2009-06, Vol.4 (6), p.e5981
• Main Authors: Radstake, Timothy R. D. J., van Bon, Lenny, Broen, Jasper, Wenink, Mark, Santegoets, Kim, Deng, Yanhui, Hussaini, Anila, Simms, Robert, Cruikshank, William W., Lafyatis, Robert
• Format: Article
• Language: English
• Subjects: Autoimmune diseases; CD25 antigen; CD3 antigen; CD4 antigen; CD69 antigen; CD8 antigen; Cytokines; Cytometry; Disease; Disease control; Flow cytometry; Foxp3 protein; Growth factors; Health risk assessment; Immunological tolerance; Immunology/Autoimmunity; Immunology/Immunomodulation; Immunoregulation; L-selectin; Lupus; Lymphocytes; Lymphocytes T; Medicine; Multiple sclerosis; Pathogenesis; Patients; Plasmas (physics); Proteins; Rheumatoid arthritis; Rheumatology; Rheumatology/Autoimmunity, Autoimmune, and Inflammatory Diseases; Rodents; Scleroderma; Subgroups; Systemic sclerosis
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0005981

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 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/Significance These 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.