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Function in Patients with Active Systemic
Deficient CD4+CD25high T Regulatory Cell
Xavier Valencia, Cheryl Yarboro, Gabor Illei and Peter E.
2007; 178:2579-2588; ;
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Print ISSN: 0022-1767 Online ISSN: 1550-6606.
Immunologists All rights reserved.
Copyright © 2007 by The American Association of
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The Journal of Immunology
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Deficient CD4?CD25highT Regulatory Cell Function in
Patients with Active Systemic Lupus Erythematosus1
Xavier Valencia,2* Cheryl Yarboro,†Gabor Illei,†‡and Peter E. Lipsky*
CD4?CD25?T regulatory cells (Tregs) play an essential role in maintaining immunologic homeostasis and preventing autoim-
munity. 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?CD25highTregs 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?CD25high
Tregs from peripheral blood of patients with active SLE as compared with normal donors and patients with inactive SLE.
Notably, CD4?CD25highTregs 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?CD25highTregs 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?CD25highTreg function in patients with active SLE, and suggest that
strategies to enhance the function of these cells might benefit patients with this autoimmune disease.
Immunology, 2007, 178: 2579–2588.
self-reactive T lymphocytes in the thymus at an early stage of
development (1, 2). Several mechanisms of peripheral tolerance
have also been described, including T cell anergy and ignorance.
In addition, studies in the murine system initially provided strong
evidence for the existence of a unique CD4?CD25?population of
naturally occurring regulatory/suppressor T cells that actively pre-
vent both the activation and the effector function of autoreactive T
cells that have escaped other mechanisms of tolerance (3–5). Re-
moval of this population from normal rodents leads to the spon-
taneous development of various autoimmune diseases both organ
specific as well as systemic. Recent studies have revealed their
presence in human peripheral blood, where they constitute up to
5% of the CD4?T cells (6, 7). These cells require cell-to-cell
contact to exert their suppressive effect in vitro. Whether or not a
soluble factor is involved depends on the experimental system
used (8, 9). Notably, the generation of CD4?CD25?T regulatory
cells (Tregs)3in the immune system is developmentally and ge-
netically controlled, as recent studies have demonstrated that the
The Journal of
he ability of the immune system to discriminate between
self and nonself is controlled by central and peripheral
tolerance mechanisms. The former involves deletion of
transcription factor FoxP3 is essential for their thymic develop-
ment (10) and is sufficient to activate a program of suppressor
function in peripheral CD4?CD25?T cells by ectopic expres-
sion (11). Genetic defects that primarily affect the development
or function of CD4?CD25?Tregs can be a primary cause of
autoimmune and other inflammatory disorders in humans (12).
However, regulation of the suppressive activity of Tregs is
more complex because in vitro activation of CD4?CD25?T
cells results in transient expression of FoxP3 but no regulatory
Systemic lupus erythematosus (SLE), the prototypical systemic
autoimmune disease, is characterized by a wide spectrum of clin-
ical manifestations and abundant production of autoantibodies to
nuclear Ags, cell surface molecules, and serum proteins (14, 15).
In SLE, it is well recognized that B cells are hyperactive and pro-
duce a variety of autoantibodies, resulting in the formation of im-
mune complexes, that play a central role in the effector phase of the
disease. Furthermore, it has also become evident that SLE T cells
participate in the attack on target cells or tissues through overpro-
duction of proinflammatory cytokines or an increase in cell-to-cell
adhesion, ultimately leading to the apoptosis of the target cells
(16). One possibility to explain the emergence of autoimmunity in
diseases such as SLE could relate to deficient function of Tregs.
The deficiency in Treg function could result in increased helper T
cell activity or directly in enhanced B cell activity, both of which
have been shown to be regulated by Tregs in normal subjects (17, 18).
Murine models that lack CD4?CD25?Tregs develop a systemic au-
toimmune disease, characterized by gastritis, oophoritis, arthritis, and
thyroiditis (5). Interestingly, some animal models lacking Treg also
develop glomerulonephritis and increased titers of anti-dsDNA (5,
19), which are hallmarks of SLE.
Initial studies in SLE suggested there was a decrease in circu-
lating CD4?CD25?T cells in patients with active disease (20, 21),
and more recently it was claimed that Treg from active SLE were
decreased in number during disease flares but displayed normal in
vitro suppressive function (22). Therefore, the potential role of
Tregs in SLE remains to be fully delineated.
*Autoimmunity Branch,†Office of the Clinical Director National Institute of Arthritis
and Musculoskeletal and Skin Diseases/National Institutes of Health, and‡Gene Ther-
apy and Therapeutics Branch, National Institute of Dental and Craniofacial Research/
National Institutes of Health, Bethesda, MD 20892
Received for publication June 13, 2006. Accepted for publication November
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.
1This work was supported by the Intramural Research Program, National Institute of
Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health.
2Address correspondence and reprint requests to Dr. Xavier Valencia, National
Institutes of Health, 10 Center Drive, Room 6D44, Bethesda, MD 20892. E-mail
3Abbreviations used in this paper: Treg, T regulatory cell; SLE, systemic lupus ery-
thematosus; SLEDAI, SLE disease activity index; GITR, glucocorticoid-induced
tumor factor receptor.
The Journal of Immunology
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2588 SLE AND CD4?CD25highTregs
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