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Deficient CD4⁺CD25^high T Regulatory Cell Function in Patients with Active Systemic Lupus Erythematosus¹

Xavier Valencia^2,*, Cheryl Yarboro, Gabor Illei^, and Peter E. Lipsky^*

^* Autoimmunity Branch, Office of the Clinical Director National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health, and Gene Therapy and Therapeutics Branch, National Institute of Dental and Craniofacial Research/National Institutes of Health, Bethesda, MD 20892

CD4⁺CD25⁺ T regulatory cells (Tregs) play an essential role in maintaining immunologic homeostasis and preventing autoimmunity. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance to nuclear components. We hypothesized that altered function of CD4⁺CD25^high Tregs might play a role in the breakdown of immunologic self-tolerance in patients with SLE. In this study, we report a significant decrease in the suppressive function of CD4⁺CD25^high Tregs from peripheral blood of patients with active SLE as compared with normal donors and patients with inactive SLE. Notably, CD4⁺CD25^high Tregs isolated from patients with active SLE expressed reduced levels of FoxP3 mRNA and protein and poorly suppressed the proliferation and cytokine secretion of CD4⁺ effector T cells in vitro. In contrast, the expression of FoxP3 mRNA and protein and in vitro suppression of the proliferation of CD4⁺ effector T cells by Tregs isolated from inactive SLE patients, was comparable to that of normal individuals. In vitro activation of CD4⁺CD25^high Tregs from patients with active SLE increased FoxP3 mRNA and protein expression and restored their suppressive function. These data are the first to demonstrate a reversible defect in CD4⁺CD25^high Treg function in patients with active SLE, and suggest that strategies to enhance the function of these cells might benefit patients with this autoimmune disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health.

² Address correspondence and reprint requests to Dr. Xavier Valencia, National Institutes of Health, 10 Center Drive, Room 6D44, Bethesda, MD 20892. E-mail address: xvalencia{at}mail.nih.gov

³ Abbreviations used in this paper: Treg, T regulatory cell; SLE, systemic lupus erythematosus; SLEDAI, SLE disease activity index; GITR, glucocorticoid-induced tumor factor receptor.

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