[From(publication date):
December-2011- Jun 19, 2013]
Breakdown by View Type
HTML Page Views :
332033
PDF Downloads : 608
XML Downloads : 390
Editorial
Open Access
Foxp3+ Regulatory T Cells: a Protagonist in the "Movie'' of Autoimmune
Diseases?
Anping Xu1, Ya Liu1,2, Bernhard Ryffel3 and Song Guo Zheng2,3*
1Division of Nephrology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, China
2Division of Rheumatology and Immunology, Department of Medicine, Keck School of Medicine at University of Southern California, USA
3University of Orléans and Molecular Immunology and Embryology, CNRS UMR6218, Orleans, France
*Corresponding author:
Dr. Song Guo Zheng
2011 Zonal Ave. HMR 711, Los
Angeles, CA 90033 Tel: 323 442 2128 Fax: 323 442 2874 E-mail: szheng@usc.edu
Received June 09, 2011; Accepted November 15, 2011; Published November
18, 2011
Citation: Xu A, Liu Y, Ryffel B, Zheng SG (2011) Foxp3+ Regulatory T Cells: a
Protagonist in the "Movie'' of Autoimmune Diseases? Rheumatology 1:e102.
doi:10.4172/2161-1149.1000e102
Although CD4+CD25+Foxp3+ regulatory or suppressor T cells
(Tregs) play a crucial role in the maintenance of self-tolerance and
immune homeostasis against self-antigen, the true role they play in
autoimmune diseases is still less defined. The prospect for therapeutic
roles of these cells in autoimmune diseases is somehow fuzzy. This
editorial will discuss and update these issues and proposes several new
directions to address the relative concerns.
Thymus-derived, naturally-occurring CD4+CD25+ suppressor cells
(nTregs) were originally described by Sakaguchi and his colleagues
where they identified that CD4+CD25+ cells in the thymus are crucial for
the control of autoimmunity [1]. As CD25 is also activation marker for
lymphocytes and therefore its expression is unable to exclude other T
effector (Teff) cell population that may contaminate Tregs. Subsequent
studies have demonstrated that Foxp3, a member of the forkhead/
winged-helix family of transcription factors, is essentially important
for the differentiation and function of Tregs, and is considered as the
best marker for their phenotypic identification so far [2-4]. Mutation
or disruption of the Foxp3 (in mouse) or FOXP3 (in human, an
analogue of Foxp3 in mouse) gene resulted in fatal lymphoproliferative
disorder in mice, and a severe multiple autoimmune disease called
immune dysregulation, polyendocrinopathy, enteropathy X-linked
syndrome (IPEX) in humans [5-7]. The abnormality in the numbers
and function of Tregs in the periphery has been widely associated with
the development and progression of many autoimmune diseases.
It is questionable whether all CD4+CD25+Foxp3+ cells in the
periphery originate from thymus. It is known that CD4+Foxp3+ T
cells can be induced through antigen stimulation in the presence of
IL-2 and TGF-β in vitro and in vivo and are known as induced Tregs
(iTregs) [8-11]. It is very likely that CD4+FOXP3+ cells circulating in
the periphery are comprised of blended nTregs and iTregs. As both
nTregs and iTreg cells express similar phenotypic characteristics, it
is difficult to distinguish nTregs from iTregs by phenotypic staining.
Recently, Thronton et al. reported that helios, an Ikaros transcription family member, may be helpful for distinguishing nTregs from iTregs
[12]. However, this ray of hope was immediately extinguished when
others found that helios is also highly expressed on Th2 and T follicular
helper cells and is associated with the differentiation of these cells [13].
Thus, the molecular makers that can distinguish both Treg subsets still
require further investigation.
As Foxp3 is considered as a best marker for Tregs in mouse, it may
not be the case for human cells. Several studies have demonstrated
that FOXP3 may be upregulated in rapidly proliferating human T
cells and might be viewed as an activation marker for human T cells
[14,15]. More studies are needed to determine whether FOXP3 is also
expressed on human Teff cells, and more specific marker(s) for human
Tregs need to be identified.
Many studies have demonstrated that the numbers and function
of CD4+FOXP3+ Tregs are abnormal in many autoimmune diseases
(Table 1). Thus, the restoration of the numbers and functional activity
of these cells may be therapeutic in autoimmune diseases since current
approaches are unable to cure these diseases. However, CD4+FOXP3+
cells are tiny cell population. Tregs must be expanded ex vivo to
gain sufficient numbers for the therapeutic consideration. Although
several groups have reported that expansion in vitro can result in
sufficient numbers of these cells [16,17], other laboratories have also
demonstrated that repeated expansion in vtiro alters Treg phenotype
and function [18]. Thus, the development of a protocol that can expand
Treg numbers and sustain Treg phenotypes and function is critically
important.
Table 1:Abnormality of numbers and function of Tregs in patients with various
autoimmune diseases.
Another problem is the stability and plasticity of Tregs. Recent
studies have demonstrated that nTregs are inherently unstable
and can be converted to Th1, Th2, Th17 and Tfh effector cells in an
inflammatory milieu [19-23]. It is reasonable to attempt to find novel
approaches to overcome the plasticity of nTregs in the inflammatory
condition. Indeed, nTregs pre-treated with IL-2 plus TGF-β or alltrans
retinoic acid (atRA), a vitamin A metabolite, are resistant to Teff
cell conversion and can suppress the progress of autoimmune diseases
[20,24], providing a potential promise that the manipulation of nTregs
may treat autoimmune diseases. However, this finding needs to be
validated in human nTregs, particularly, in nTregs from patients with
autoimmune diseases.
The suppressive activity of nTregs can be disrupted with proinflammatory
cytokines. For example, Pasare et al. have reported that
Treg suppressive activity can be abolished by IL-6 [25]. Valencia et al.
also revealed that elevated TNF-α may interfere with the suppressive
capacity of nTregs [26]. There is no question that these proinflammatory
cytokines are elevated in many autoimmune diseases.
Future studies will be needed to determine whether the combination
of Treg therapy and anti-inflammatory cytokine therapy results in best
therapeutic effect, or treatment of patient using anti-inflammatory
cytokine antibodies first, sequentially use Treg cell treatment may
restore and/or enhance their therapeutic effect on autoimmune
diseases.
Acknowledgements
We thank Dr. William Stohl at University of Southern California for his critical
comment. This work was partially supported by grants from the NIH R01 AR
059103, Arthritis Foundation; Wright Foundation; the Arthritis National Research
Foundation; the Clinical Research Feasibility Fund; the James H. Zumberge
Faculty Research and Innovation Fund; the Outstanding Youth Scientist Award
from National Nature Science Foundation of China (30728007), the American
College of Rheumatology Research and Education’s Within Our Reach: Finding
a Cure for Rheumatoid Arthritis campaign (all to SGZ) as well as Le Studium and
European FEDER grant support (BR).
OMICS Publishing Group is the member of / publishing partner of/source content provider to
OMICS Publishing Group, An Open Access Publisher and Scientific Events Organizer for the Advancement of Science & Technology. All Published content, except where otherwise noted, is licensed under a Creative Commons Attribution License
Please ensure that you are using the latest version of Adobe reader. If you do not have this software installed on your system, you can download the free Adobe Reader by simply clicking on the following link: http://www.adobe.com/products/acrobat/readstep2.html
