Nat Clin Pract Cardiovasc Med. 2008 Jul 8
Mechanisms of Disease: the evolving role of regulatory T cells in
atherosclerosis.
George J; Medscape.
J George is Professor of Cardiology at the Department of Cardiology and
the Cardiovascular Research Center, Tel Aviv Sourasky Medical Center and
the Sackler Faculty of Medicine, Tel Aviv University, Israel.
Atherosclerosis and related complications still represent the major
cause of morbidity and mortality in the western world. The mechanisms
that govern the progression and destabilization of atheromatous lesions
are multiple and complex. Despite their widespread use, lipid-lowering
agents do not provide sufficient protection from future clinical
cardiovascular-associated events. Interest in the role of immunity in
atherosclerosis and sup****t for this relation****p has grown
significantly over recent years. This paradigm, in which inflammation is
an instrumental process in plaque development and rupture, is further
sup****ted by studies showing that immune subsets are operative in
atherosclerosis. Regulatory T-cell subpopulations consist of
lymphocytes-with several phenotypic markers-that share the ability to
suppress, by various mechanisms, inflammatory responses. These
regulatory T cells consist of subsets such as interleukin-10 secreting
type I regulatory cells, type 3 effector T-helper cells that produce
transforming growth factor-beta, as well as adaptive and natural
CD4(+)CD25(+) regulatory T cells. In this Review, I focus on the direct
and indirect evidence for the involvement of regulatory T cells in
atherogenesis in experimental models and in humans. The growing
knowledge of the role of regulatory T cells could result in the future
development of novel therapeutic modalities to attenuate atherosclerosis
and stabilize vulnerable plaques.
PMID: 18607396
Curr Atheroscler Rep. 2008 Jun;10(3):236-43.
The complex role of T-cell-based immunity in atherosclerosis.
Aukrust P, Otterdal K, Yndestad A, Sandberg WJ, Smith C, Ueland T, Oie
E, Damas JK, Gullestad L, Halvorsen B.
Rikshospitalet University Hospital, N-0027 Oslo, Norway.
Although the pathogenic role of T cells in atherogenesis is well
established, the function of the various T-cell subsets is far from
clear. Whereas activation of the T-helper type 1 (Th1) subset promotes
inflammatory and proatherogenic responses and activation of Th2 cells
mediates both proatherogenic and antiatherogenic effects, the newly
discovered regulatory T-cell subset seems to attenuate atherogenesis.
However, the dynamics of T-cell response within the plaque are still
poorly understood, and both antigen-dependent and antigen-independent
stimuli may be involved in the expansion of T cells in atheroscl*****c
plaques. Nevertheless, the different nature of the various T-cell
subsets and their complex role in atherogenesis underscore the need for
future research in this field of atheroimmunology. This research is not
only of interest for the basic research field, but may also have
relevance for clinical cardiology, potentially leading to new targets
for therapy in atheroscl*****c disorders.
PMID: 18489852
J Intern Med. 2008 May;263(5):489-99. Related Articles, LinkOut
Regulatory T-cell immunity and its relevance to atherosclerosis.
Taleb S, Tedgui A, Mallat Z.
Centre de Recherche Cardiovasculaire Lariboisiere, Inserm U689, Paris,
France.
Atherosclerosis is a chronic inflammatory disease of the arterial wall
where both innate and adaptive immune responses contribute to disease
initiation and progression. Recent studies from several groups suggest
that subtypes of T cells, called regulatory T cells, previously shown to
maintain immunological tolerance, inhibit the development and
progression of atherosclerosis. Here, we review the current knowledge on
the regulatory T-cell response and the major cytokines involved in its
modulation in the context of atherosclerosis.
Publication Types:
* Review
PMID: 18410592
Clin Immunol. 2008 Apr;127(1):89-97. Epub 2008 Feb 21.
The Th17/Treg imbalance in patients with acute coronary syndrome.
Cheng X, Yu X, Ding YJ, Fu QQ, Xie JJ, Tang TT, Yao R, Chen Y, Liao YH.
Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union
Hospital, Tongji Medical College, Huazhong University of Science and
Technology, Wuhan 430022, China.
Atherosclerosis is a chronic inflammatory disease regulated by T
lymphocyte subsets. Recently, CD4+CD25+Foxp3+ regulatory T (Treg) cells
and Th17 cells have been described as two distinct subsets from Th1 and
Th2 cells and have the opposite effects on autoimmunity. Th17/Treg
balance controls inflammation and may be im****tant in the pathogenesis
of plaque destabilization and the onset of acute coronary syndrome [ACS,
including unstable angina (UA) and acute myocardial infarction (AMI)].
To *****s whether this balance was broken in patients with coronary
heart disease, we detected Th17/Treg functions on different levels
including cell frequencies, related cytokine secretion and key
transcription factors in patients with AMI, UA, stable angina (SA) and
controls. The results demonstrated that patients with ACS revealed
significant increase in peripheral Th17 number, Th17 related cytokines
(IL-17, IL-6 and IL-23) and transcription factor (RORgammat) levels and
obvious decrease in Treg number, Treg related cytokines (IL-10 and
TGF-beta1) and transcription factor (Foxp3) levels as compared with
patients with SA and controls. Results indicate that Th17/Treg
functional imbalance exists in patients with ACS, suggesting a potential
role for Th17/Treg imbalance in plaque destabilization and the onset of
ACS.
Publication Types:
* Research Sup****t, Non-U.S. Gov't
PMID: 18294918
Circulation. 2007 Oct 9;116(15):1707-13. Epub 2007 Sep 17.
Measles virus nucleoprotein induces a regulatory immune response and
reduces atherosclerosis in mice.
Ait-Oufella H, Horvat B, Kerdiles Y, Herbin O, Gourdy P, Khallou-Laschet
J, Merval R, Esposito B, Tedgui A, Mallat Z.
Inserm U689, Centre de Recherche Cardiovasculaire Lariboisiere, Hopital
Lariboisiere, 41, Bd de la Chapelle, 75010 Paris, France.
BACKGROUND: Recent studies clearly suggest that regulatory T cells play
a critical role in the control of the immunoinflammatory response in
atherosclerosis and substantially limit lesion development. Measles
virus infection or vaccination is associated with immune depression, in
part through the induction of an antiinflammatory response by measles
virus nucleoprotein. We hypothesized that the antiinflammatory
properties of measles virus nucleoprotein may limit the development
atherosclerosis. METHODS AND RESULTS: Here, we show for the first time
that repetitive administration of measles virus nucleoprotein to
apolipoprotein E-deficient mice promotes an antiinflammatory
T-regulatory-cell type 1-like response and inhibits macrophage and
T-cell ac***ulation within the lesions. Treatment with measles virus
nucleoprotein significantly reduces the development of new
atheroscl*****c plaques and markedly inhibits the progression of
established lesions. The antiatheroscl*****c potential of nucleoprotein
is retained in its short N-terminal segment. The protective effects on
lesion size are lost in mice with lymphocyte deficiency. CONCLUSIONS:
Our findings identify a novel mechanism of immune modulation by measles
virus nucleoprotein through the promotion of a regulatory T-cell
response and suggest that this property may be harnessed for treating
atherosclerosis, the first cause of heart disease and stroke.
Publication Types:
* Research Sup****t, Non-U.S. Gov't
PMID: 17875970 [PubMed - indexed for MEDLINE]
PLoS ONE. 2007 Aug 22;2(1):e779.
Low numbers of FOXP3 positive regulatory T cells are present in all
developmental stages of human atheroscl*****c lesions.
de Boer OJ, van der Meer JJ, Teeling P, van der Loos CM, van der Wal AC.
Department of Pathology, Academic Medical Center, University of
Amsterdam, Amsterdam, The Netherlands.
BACKGROUND: T cell mediated inflammation contributes to atherogenesis
and the onset of acute cardiovascular disease. Effector T cell functions
are under a tight control of a specialized T cell subset, regulatory T
cells (Treg). At present, nothing is known about the in situ presence of
Treg in human atheroscl*****c tissue. In the present study we
investigated the frequency of naturally occurring Treg cells in all
developmental stages of human atheroscl*****c lesions including
complicated thrombosed plaques. METHODOLOGY: Normal arteries, early
lesions (American Heart Association classification types I, II, and
III), fibroscl*****c plaques (types Vb and Vc) and 'high risk' plaques
(types IV, Va and VI) were obtained at surgery and autopsy. Serial
sections were immunostained for markers specific for regulatory T cells
(FOXP3 and GITR) and the frequency of these cells was expressed as a
percentage of the total numbers of CD3+ T cells. Results were compared
with Treg counts in biopsies of normal and inflammatory skin lesions
(psoriasis, spongiotic dermatitis and lichen planus). PRINCIPLE
FINDINGS: In normal vessel fragments T cells were virtually absent. Treg
were present in the intima during all stages of plaque development
(0.5-5%). Also in the adventitia of atheroscl*****c vessels Treg were
encountered, in similar low amounts. High risk lesions contained
significantly increased numbers of Treg compared to early lesions (mean:
3.9 and 1.2%, respectively). The frequency of FOXP3+ cells in high risk
lesions was also higher compared to stable lesions (1.7%), but this
difference was not significant. The mean numbers of intimal FOXP3
positive cells in atheroscl*****c lesions (2.4%) was much lower than
those in normal (24.3%) or inflammatory skin lesions (28%). CONCLUSION:
Low frequencies of Treg in all developmental stages of human plaque
formation could explain the smoldering chronic inflammatory process that
takes place throughout the longstanding course of atherosclerosis.
PMID: 17712427 [PubMed]
Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2691-8. Epub 2007 Aug 9.
Comment in:
* Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2493-5.
Defective leptin/leptin receptor signaling improves regulatory T cell
immune response and protects mice from atherosclerosis.
Taleb S, Herbin O, Ait-Oufella H, Verreth W, Gourdy P, Barateau V,
Merval R, Esposito B, Clement K, Holvoet P, Tedgui A, Mallat Z.
Institut National de la Sante et de la Recherche Medicale, U689, 41 Bd
de la Chapelle, Paris, France.
OBJECTIVE: Obesity is a major risk factor for atherosclerosis and is
associated with increased cardiovascular morbidity and mortality.
However, the precise molecular pathways responsible for this close
association remain poorly understood. METHODS AND RESULTS: In this
study, we re****t that leptin-deficiency (ob/ob) in low-density
lipoprotein receptor knockout (ldlr(-/-)) mice induces an unexpected
2.2- to 6-fold reduction in atheroscl*****c lesion development, compared
with ldlr(-/-) mice having similar total cholesterol levels.
Ldlr(-/-)/ob/ob mice show reduced T cell helper type 1 (Th1) response,
enhanced expression of Foxp3, the specification transcription factor of
regulatory T (Treg) cells, and improved Treg cell function. Leptin
receptor-deficient (db/db) mice display marked increase in the number
and suppressive function of Treg cells. Supplementation of
Treg-deficient lymphocytes with Treg cells from db/db mice in an
experimental model of atherosclerosis induces a significant reduction of
lesion size and a marked inhibition of interferon (INF)-gamma
production, compared with supplementation by Treg cells from wild-type
mice. CONCLUSIONS: These results identify a critical role for
leptin/leptin receptor pathway in the modulation of the regulatory
immune response in atherosclerosis, and suggest that alteration in
regulatory immunity may predispose obese individuals to atherosclerosis.
Publication Types:
* Research Sup****t, Non-U.S. Gov't
PMID: 17690315
Cell Immunol. 2006 Oct;243(2):90-5. Epub 2007 Feb 26.
Generation of HSP60-specific regulatory T cell and effect on
atherosclerosis.
Yang K, Li D, Luo M, Hu Y.
Department of Cardiology, Institute of Cardiovascular Diseases, Union
Hospital, Tongji Medical College, Huazhong University of Science and
Technology, Wuhan 430022, PR China.
Although CD4(+)CD25(+) regulatory T cells are pivotal in the suppression
of autoimmunity, little is known about the effect of antigen-specific
regulatory T cells on the formation of atheromatous plaques. Here, we
describe the induction of heat-shock protein 60 (HSP60)-specific
CD4(+)CD25(high) T cells by rapamycin (RPM)-treated immature dendritic
cells in vitro and explore their effect on plaques in apolipoprotein
E-deficient mice. Rapamycin-treated bone marrow-derived dendritic cells
(DC) were immature, expressing a low level of co-stimulation factors
CD86 and CD80. Naive CD4(+) T cells expressed high levels of CD25 and
forkhead box P3 (Foxp3) after incubation with rapamycin-treated and
HSP60-loaded DC and displayed moderate antigen-specific,
IL-10-independent inhibitory function in vitro. After adoptive transfer,
HSP60-specific CD4(+)CD25(high) T cells inhibited the formation of
plaques, while ovalbumin-specific cells did not. These findings suggest
that RPM-treated DC can induce antigen-specific CD4(+)CD25(high) Treg
cells that have inhibitory activity in vitro and prevent the development
of plaques in vivo.
PMID: 17324390
Arterioscler Thromb Vasc Biol. 2007 Apr;27(4):893-900. Epub 2007 Feb 1.
Role of naturally occurring CD4+ CD25+ regulatory T cells in
experimental atherosclerosis.
Mor A, Planer D, Lubo****s G, Afek A, Metzger S, Chajek-Shaul T, Keren
G, George J.
Department of Cardiology, Tel Aviv Sourasky Medical Center, Sackler
School of Medicine, Tel Aviv University, Tel Aviv, Israel.
OBJECTIVE: Naturally occurring CD4+ CD25+ regulatory T cells (Tregs)
exert suppressive effects on effector CD4 cells and downregulate
experimental autoimmune disorders. We investigated the im****tance and
potential role of Tregs in murine atherogenesis. METHODS AND RESULTS:
Tregs were investigated comparatively between aged and young
apolipoprotein E-knockout (ApoE-KO) mice and age-matched C57BL/6
littermates. The effect of oxidized LDL (oxLDL) was tested on the
functional suppressive properties of Tregs from ApoE-KO and C57BL/6
mice. Tregs, CD4+ CD25- cells, and saline were infused into ApoE-KO mice
to study their effects on atherogenesis. Treg numbers were reduced in
atheroscl*****c compared with nonatheroscl*****c ApoE-KO mice. The
functional suppressive properties of Tregs from ApoE-KO mice were
compromised in comparison with those from their C57BL/6 littermates.
Thus, oxLDL attenuated the suppressive properties of Tregs from C57BL/6
mice and more so in ApoE-KO mice. Transfer of Tregs from age-matched
ApoE-KO mice resulted in significant attenuation of atherosclerosis
compared with that after delivery of CD4+ CD25+/- T cells or
phosphate-buffered saline. CONCLUSIONS: CD4+ CD25+ Tregs may play a
protective role in the progression of atherosclerosis and could be
considered a therapeutic tool if results from human studies can solidify
observations in murine models.
Publication Types:
* Research Sup****t, Non-U.S. Gov't
PMID: 17272749
Circulation. 2006 Oct 31;114(18):1977-84. Epub 2006 Oct 16.
Comment in:
* Circulation. 2006 Oct 31;114(18):1901-4.
Short-term treatment with anti-CD3 antibody reduces the development and
progression of atherosclerosis in mice.
Steffens S, Burger F, Pelli G, Dean Y, Elson G, Kosco-Vilbois M,
Chatenoud L, Mach F.
Division of Cardiology, Department of Medicine, University Hospital,
Foundation for Medical Researches, 64 Avenue Roseraie, 1211 Geneva,
Switzerland.
BACKGROUND: Atherosclerosis is a chronic inflammatory disease of the
large arteries that is the primary cause of heart disease and stroke.
Anti-CD3-specific antibodies suppress immune responses by antigenic
modulation of the CD3 antibody/T-cell receptor complex. Their unique
capacity to restore self-tolerance in a mouse model of diabetes and,
im****tantly, in patients with recent-onset type 1 diabetes involves
transforming growth factor-beta-dependent mechanisms via expansion
and/or activation of regulatory T cells. We hypothesized that treatment
with anti-CD3-specific antibodies might inhibit atherosclerosis
development and progression in mice. METHODS AND RESULTS: Low-density
lipoprotein receptor-deficient mice were fed a high-cholesterol diet for
13 or 24 weeks. Anti-CD3 antibody was administered on 5 consecutive days
beginning 1 week before or 13 weeks after the high-cholesterol diet was
initiated, respectively. Control mice were injected in parallel with
phosphate-buffered saline. Anti-CD3 antibody therapy reduced plaque
development when administered before a high-cholesterol diet and
markedly decreased lesion progression in mice with already established
atherosclerosis. We found increased production of the antiinflammatory
cytokine transforming growth factor-beta in concanavalin A-stimulated
lymph node cells and enhanced expression of the regulatory T-cell marker
Foxp3 in spleens of anti-CD3 antibody-treated mice. A higher percentage
of apoptotic cells within the plaques of anti-CD3 antibody-treated mice
was also observed. CONCLUSIONS: Altered disease progression, combined
with the emergence of this particular cytokine pattern, indicates that
short-term treatment with an anti-CD3 antibody induces a regulatory
T-cell phenotype that restores self-tolerance in a mouse model of
atherosclerosis.
Publication Types:
* Research Sup****t, Non-U.S. Gov't
PMID: 17043169
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