FEMS Immunology and Medical Microbiology 44 (2005) 121–127
www.fems-microbiology.org
MiniReview
CD4+CD25+ suppressor T cells regulate pathogen
induced inflammation and disease
Sukanya Raghavan *, Jan Holmgren
Department of Medical Microbiology and Immunology, The Göteborg University Vaccine Research Institute (GUVAX),
P.O. Box 435, 405 30 Göteborg, Sweden
Received 1 August 2004; received in revised form 14 October 2004; accepted 18 October 2004
First published online 23 November 2004
Abstract
A key suppressor role has recently been ascribed to the natural CD4+CD25+ regulatory T cells (Treg), the removal of which leads
to the development of autoimmune disease and aggravated pathogen-induced inflammation in otherwise normal hosts. The repertoire of antigen specificities of Treg is as broad as that of naı̈ve T cells, recognizing both self and non-self antigens, enabling Treg to
control a broad range of immune responses. Although widely acknowledged to play a role in the maintenance of self-tolerance,
recent studies indicate that Treg can be activated and expanded against bacterial, viral and parasite antigens in vivo. Such pathogen-specific Treg can prevent infection-induced immunopathology but may also increase the load of infection and prolong pathogen
persistence by suppressing protective immune responses. This review discusses the role of Treg in the prevention of exaggerated
inflammation favoring chronicity in bacterial or fungal infections and latency in viral infections. Special attention is given to the
role of Treg in the modulation of gastric inflammation induced by Helicobacter pylori infection. Findings in both experimentally
infected mice and humans with natural infection indicate that Treg are important in protecting the H. pylori-infected host against
excessive gastric inflammation and disease symptoms but on the negative side promote bacterial colonization at the gastric and duodenal mucosa which may increase the risk in H. pylori-infected individuals to develop duodenal ulcers.
Ó 2004 Federation of European Microbiological Societies. Published by Elsevier B.V. All rights reserved.
Keywords: CD4+CD25+ regulatory T cells; Helicobacter pylori; Gastritis; Duodenal ulcer; Cytokines; Pathogens; Immunization
1. Introduction
A major mechanism for self/non-self discrimination
by the immune system and establishment of self tolerance
is the clonal deletion of self reactive T and B cells exposed
to self antigens during development in the thymus [1].
The deletion mechanism is not complete however, and
potentially hazardous self-reactive lymphocytes are present in the periphery of normal individuals. It has become
increasingly evident that active suppression of selfreactive T cells by regulatory T cells takes place in the
*
Corresponding author. Tel.: +46 31 7736230; fax: +46 31 7736210.
E-mail address: [email protected] (S. Raghavan).
periphery of normal individuals avoiding the onset of
harmful autoimmunity. Several phenotypically distinct
subsets of suppressor-regulatory T cells have been described based on one or more surface marker antigens
and/or cytokine production profiles; for e.g., the natural
CD4+CD25+ T regulatory cells (Treg) [2], the IL-10
secreting Tr1 cells [3] and the TGF-b secreting Th3 cells
[4], which functionally both in vitro and in vivo have
been shown to suppress the proliferation and cytokine
secretion of effector T cells.
However, an accumulating body of evidence now
indicates that the most important among these regulatory T cells are the unique lineage of thymus-derived
CD4+CD25+ T cells referred to as natural regulatory
0928-8244/$22.00 Ó 2004 Federation of European Microbiological Societies. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.femsim.2004.10.017
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S. Raghavan, J. Holmgren / FEMS Immunology and Medical Microbiology 44 (2005) 121–127
T cells (Treg) [5]. Treg constitutively co-express several
cell surface markers (Table 1) that allows for their discrimination and subsequent isolation for carrying out
functional studies [6]. In vivo, Treg were first identified
based on their active suppression of self-reactive T cells
in normal mice. Removal of thymus at day 3 of life in
mice or transfer of T cells depleted of Treg to immune
deficient animals resulted in wide spread autoimmune
disease. Co-transfer of Treg together with the pathogenic cells prevented autoimmune disease proving the
unequivocal role of Treg in the prevention of harmful
immune reactivity to self in normal mice [2,7]. Recent
studies suggest that Treg are also important in the
induction of other regulatory T cells such as Tr1 and
Th3 cells (see below). Treg have also been purified and
characterized from the peripheral blood [8,9], thymus
[9,10] and the cord blood [9] of humans. Interestingly,
cord blood Treg have reduced suppressive efficacy compared to Treg isolated from peripheral blood suggesting
that further differentiation and expansion of the Treg
may take place in the periphery [11].
2. Characteristics and functions of Treg in vitro and
in vivo
In vitro Treg from both mice and humans are anergic
to stimulation via their TCR and further inhibit
CD4+CD25 T cell responses to anti-CD3 stimulation
[12,13]. Suppression is cell contact dependant and occurs
only when Treg are activated through their T cell receptor (TCR) [12]. Several studies have shown that, Treg
fail to suppress if they are fixed with formaldehyde before activation or if they are cultured with an antigen
other than their specificity [8,12]. The suppression of
CD25 responses by Treg can be overcome by addition
of IL-2 in culture or by enhancing endogenous IL-2 production by the addition of anti-CD28 antibody [12,14].
Recent evidence suggests that in contrast to the in vitro observations, Treg are not anergic to stimulation via
their TCR in vivo and can proliferate as extensively as
naı̈ve T cells in response to immunization [15,16]. Interestingly, in spite of antigen specific proliferation in vivo,
Treg failed to produce any IL-2 or effector cytokines and
do not upregulate CD40L. Thus, after immunization
while CD4+CD25 T cells expand and acquire effector
T cell phenotype, Treg expand but do not adopt a phenotype consistent with the provision of T cell help to
CD8+ cells or B cells [17]. In addition, in vivo expanded
Treg retain their suppressive function in vitro [18].
Murine scurfy and human IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) are X-linked recessive disorders of immune
regulation. Efforts to identify genetic defects in IPEX
patients or scurfy mice have revealed mutations in the
Foxp3 gene (FOXP3 in humans) encoding a novel and
highly conserved protein called scurfin [19]. Several
studies in both mice and humans have shown that the
Foxp3 gene is constitutively and specifically expressed
in natural Treg and play an indispensable role in their
development and furthermore, the ectopic expression
of the Foxp3 gene in CD4+CD25 T cells resulted in cells
with a Treg phenotype and function [20]. However,
there are still some conflicting reports as to whether
the expression of Foxp3 gene is exclusive to Treg or
could induced regulatory T cells that have acquired suppressor function also express Foxp3. In a recent study,
Apostolou and Von Boehmer [21] have shown in TCR
transgenic mice specific for the hemagglutinin peptide
that CD4+CD25 induced suppressor T cells express
the Foxp3 gene transcript. Thus, consensus in this area
of research is that even though Foxp3 could be expressed
by suppressor T cells that are not ‘‘natural’’ thymus derived Treg; it still confers on the T cells a suppressor
phenotype.
The mechanism of suppression by Treg has been a
subject of intense investigation in several laboratories
these past few years. Studies both in humans and animal
models suggest that Treg exert their effect through a cell
contact dependent mechanism. However considering
their low frequency (5–10% of the CD4+ T cells), it
seems unlikely that this is the main mechanism leading
to both local and systemic suppression. Through some
elegant experiments Dieckmann et al. [22] and Jonuleit
et al. [23] have shown that suppression by Treg in humans could take place in two steps. The first step is cell
contact dependent; perhaps mediated through cell surface bound TGF-b, and involves the ‘‘education’’ of
CD4+ T helper cells to become induced suppressor cells
(Tsup). In the next step Tsup cells then exert their
suppressive effects on effector T cells in a cell contact
independent manner through the secretion of cytokines
IL-10 and TGF-b. In addition, it has also been shown
in humans that Treg in the peripheral blood can be separated based on their surface expression of homing
receptors, a4b7 (mucosal homing) and a4b1 (peripheral
Table 1
Cell surface and intracellular markers constitutively expressed by thymus derived natural Treg
Species
Cell surface
Intracellular
Murine
CD25+, CD122+, CD69+, CD44+, CD45RBlow, GITR+,
CD103+(aE-integrin), CD134+(OX-40), CD54+(ICAM)
CD25high, CD122+, HLA-DR+(50%), CD45RO+(80%),
CD95high, CD45RBlow, CD38low, partly CD62low, GITR+
CTLA-4+, Foxp3+
Human
CTLA-4+, FOXP3+
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homing). Both populations of sorted Treg were able to
confer suppressive capacity on conventional CD4+ T
cells converting them to Tsup cells [24]. Interestingly,
a4b7 sorted Treg, induced IL-10 producing (Tr1 like)
Tsup cells and a4b1 sorted Treg induced TGF-b producing (Th3 like) Tsup cells, respectively. Thus, in healthy
individuals, circulating peripheral Treg inducing TGFb secreting Th3 like Tsup cells could play a central role
in preventing autoimmunity, and the mucosa-homing
Treg inducing IL-10 secreting Tr1 like Tsup cells could
play a more important role in the prevention of intestinal inflammation including IBD [24].
3. The role of Treg in the modulation of pathogen induced
inflammation
The recognition of an important role for regulatory T
cells in the suppression of pathogen induced inflammatory responses has just started to emerge. Recent evidence suggests that the activation of regulatory T cells
including both Treg and Tr1 cells might result in decreased pathological responses and prolonged persistence of infection as a mechanism for the maintenance
of pathogen specific immunologic memory. In a study
by Mc Guirk et al. [25] Tr1 clones specific for filamentous hemagglutinin and pertactin could be isolated from
the lungs of mice chronically infected with Bordetella
pertussis. These Tr1 clones produced high levels of IL10 but not IL-4 or IFN-c and suppressed Th1 responses
in vitro to B. pertussis or an unrelated pathogen. A role
for Treg cells in the modulation of immune responses to
pathogens has also been described in two different murine models of infection caused by Leishmania major and
Pneumocystis carini. In both models it was shown that
the depletion of Treg resulted in a reduction of the infection load but at the cost of more severe inflammation
[26,27]. In addition, Belkaid et al. [28] in their study
made an important observation that, the development
of a memory immune response to cutaneous Leishmania
major infection in mice was dependant on the presence
Treg. Thus, although Treg down regulate inflammation
and promote persistence of the pathogen, the memory
response generated due to antigen persistence is crucial
for protection against a second encounter with the same
pathogen.
Until now, most studies have focused on the role of
Treg in the suppression of CD4+ T cell responses against
infectious agents, but there is recent evidence indicating
that Treg are also capable of suppressing effector CD8+
T cell responses. Kursar et al. [29] reported in a murine
model of intracellular Listeria monocytogenes infection
that the CD8+ responses to the pathogen is under the
control of Treg. This observation was rather serendipitous as they first observed that depleting CD4+ T cells
in L. monocytogenes infected mice enhanced the CD8+
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T cell responses specifically to listeriolysin antigen. Further investigation revealed that depletion of CD4+ T
cells in vivo indeed affected the numbers of CD4+CD25+
expressing Treg and overcame the suppressive effects of
Treg on the expansion of effector CD8+ T cell responses.
It is interesting to note that similar depletion of Treg
(using anti-CD25 antibody) resulted in only modest elevation in the CD8+ T cell responses in these mice in response to L. monocytogenes infection. The authors
hypothesize that although depletion of CD25+ T cells
targets specifically Treg, the depletion achieved was only
75% compared to 90% depletion achieved with the
CD4+ antibody. Alternatively, one could speculate an
additional role for CD4+CD25 regulatory T cells, such
as Tr1 or Th3 cells, in the mice treated with anti-CD25
antibody, on the suppression of CD8+ T cell responses,
which to our knowledge has not yet been investigated.
In addition to intracellular infections, Treg are also
known to play a role in the control of CD8+ T cell responses to viral infections. A study by Suvas et al. [30]
showed that the depletion of Treg in vivo before infection with Herpes simplex virus-1 (HSV-1) resulted in significantly enhanced CD8+ T cell responses to the
immunodominant peptide. Interestingly in their study
Treg isolated from chronically HSV-1 infected mice
had enhanced suppressive activity against CD8+ T cell
proliferative responses to the immunodominant HSV
peptide in vitro compared to Treg isolated from uninfected naive mice. The authors propose that chronic viral infection leads to the induction and expansion of Treg
in vivo that in turn inhibit antiviral immune responses.
Whether depletion of Treg during chronic viral infections could a beneficial immunological intervention to
the host is still a matter of debate. Further studies need
to be carried out on the effects of Treg depletion and the
side effects to the host before it could be considered as a
treatment approach in humans.
How do Treg selectively suppress autoimmune responses or excessive antimicrobial responses, but still allow the development of protective responses against
invading pathogenic microbes? This question was answered to some extent by a study by Caramalho et al.
[31] showing that Treg in normal mice selectively express
Toll-like receptor (TLR) 4, 5, 7 and 8, while TLR 1, 2
and 6 appear to be more broadly expressed on CD4+
T cells. As a consequence of expressing TLR-4, Treg respond in vitro to lipopolysaccharide (LPS) stimulation,
which elicits proliferation, enhanced survival and also
increased suppressive capacity. However, it is also
known that LPS stimulation of dendritic cells (DC) triggers their maturation leading to increased MHC expression and induction of co stimulatory molecules such as
CD80 and CD86. Thus it seems evident that stimulation
through TLR has different effects on the immune responses, (i) to trigger DC maturation and augment T
cell mediated adaptive immunity and (ii) to activate
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Treg and thereby down-regulate immune responses.
Although these effects are apparently conflicting, the
concentration of LPS required for evoking the proliferation of Treg is several orders of magnitude higher than
the concentration required for in vitro activation of DC
[31]. It is therefore likely that upon gram-negative bacterial infection, LPS stimulation of TLR on DC will stimulate maturation of DC thereby inducing the activation
and expansion and differentiation of microbe specific naı̈ve T cells together with LPS-specific B cell antibody responses. If a large enough amounts of LPS is present,
e.g., as a result of successful attack of the pathogen by
antibody and complement, Treg having a higher threshold for activation will respond to LPS through TLR and
increase their suppressive activity and thereby prevent
local or systemic immunopathology.
Treg can also be considered to be harmful to the host
as pathogens can take advantage of the suppressive effects of Treg and impair immune responses and eradication of the infection. For example patients with an
ongoing malaria infection frequently show reduced immune responses not only to the malarial parasite but
also to unrelated antigens suggesting that an active T
cell suppressive mechanism operates during the course
of malaria infection. In a mouse model of Plasmodium
yoelii infection, Hisaeda et al. [32] addressed whether
Treg are the mediators of immune suppression observed
during malaria infection. Interestingly, wild type mice
that were infected with a lethal dose of P. yoelii all died,
while depletion of Treg resulted in rescue of 80% of the
infected mice with resulting eradication of the parasite
from the blood [32].
4. The function of Treg in the regulation of Helicobacter
pylori induced gastric inflammation
Helicobacter pylori, a spiral gram negative bacterium,
colonizes the human stomach and duodenum and causes
chronic inflammation, gastric atrophy and peptic ulcers
in a sub-population of infected individuals [33]. The
infection is acquired during early childhood and is usually life-long. Although half the worldÕs population is infected with this bacterium only approximately 10–15%
of those colonized develop symptoms and the rest of
the population is designated as ‘‘asymptomatic carriers’’[33]. It is attractive to speculate, supported by data
from an experimental infection model that the activation
of Treg in asymptomatic carriers keeps the pathology
mild enough to avoid symptoms [34,35].
In our laboratory Lundgren et al. [36] have shown in
H. pylori infected asymptomatic individuals, that the
memory T cell responses to H. pylori antigens in the
peripheral blood is under the control of Treg. Removal
of Treg specifically from the memory T cell population
increased the proliferative responses to H. pylori anti-
gens and importantly, addition of Treg back to the
memory T cells suppressed the H. pylori specific responses but failed to suppress responses to unrelated
antigens. In addition, CD4+CD25high T cells (putative
Treg) isolated from the gastric and duodenal mucosa
of H. pylori infected asymptomatic carriers express the
specific Treg marker FOXP3, supporting an important
role for Treg in maintaining a balance between chronicity and development of symptoms at the site of infection
[34].
We and others have previously shown in a mouse
model of H. pylori infection that mucosal immunization
with H. pylori antigen together with an adjuvant results
in protection against H. pylori infection resulting in reduced bacterial loads but not complete eradication
[37,38]. However the reduction in bacterial load
achieved as a result of immunization is associated with
inflammation in the gastric mucosa referred to postimmunization gastritis due to an expansion of H. pylori
specific T cells that migrate to the gastric mucosa to perform their effector functions [38]. However, a study by
Garhart et al. [37], clearly showed that post-immunization gastritis resolves after a few months with low levels
of bacteria remaining in the stomach.
To address the role of Treg in the modulation of immune response to H. pylori infection we used a H. pylori
antigen specific in vitro co-culture assay, wherein Treg
were mixed with CD4+CD25 effector cells and antigen
presenting cells (APC). Using this system, we have recently been able to test the hypothesis of a defective Treg
function in H. pylori infected mice after immunization.
Our results conclusively showed that Treg from naı̈ve
mice and less efficiently from infected mice suppressed
the CD25 effector T cell response to H. pylori antigens,
while Treg isolated from the H. pylori immunized mice
were the least efficient in suppressing H. pylori specific
CD25 effector T cell proliferation and cytokine secretion [35]. We suggest based on our results, that post
immunization gastritis in vivo could be attributed to a
defective Treg function leading to uncontrolled effector
T cell responses to H. pylori antigens, while suppression
of H. pylori specific responses by Treg in naı̈ve mice may
enhance the susceptibility to infection.
The reason for the highest efficacy of Treg isolated
from naı̈ve mice in the suppression of CD25 effector
T cell responses to H. pylori antigen is not clear. The
mice used for these studies were specific pathogen free
(SPF) but not Helicobacter free, and could thus have a
low-grade infection in the intestine with naturally infecting Helicobacter sps such as H. hepaticus. Kullberg et al.
[39] have recently shown using a H. hepaticus model of
intestinal inflammation in IL-10 / mice that Treg are
essential in the down-regulation of H. hepaticus driven
intestinal inflammation. Thus, in naı̈ve mice it is reasonable to assume that chronic H. hepaticus infection in the
intestine expand Helicobacter specific Treg in vivo that
S. Raghavan, J. Holmgren / FEMS Immunology and Medical Microbiology 44 (2005) 121–127
cross-recognize H. pylori antigens and suppress effector
T cell proliferation in vitro.
The site of Treg suppression of effector immune cells
secreting pro-inflammatory cytokines and driving gastric inflammation is not yet known. H. pylori specific
Treg may be activated in the draining lymph nodes of
the gastrointestinal tract (mesenteric lymph nodes,
MLN) and in turn inhibit DC activation and lifespan,
preventing the further activation and development of
effector T cells. Alternatively they may act locally in
the gastric mucosa inhibiting T-effector cell function,
particularly macrophage activation (Fig. 1). Given the
potent pro-inflammatory milieu in the gastric mucosa
of H. pylori infected individuals, it seems likely that Treg
would have to work at multiple sites to perform their
125
suppressor function to effectively down regulate H. pylori induced inflammation. In addition, it is possible in
H. pylori induced inflammation in the stomach, that
Treg specific for both H. pylori antigens and self antigens are activated [40] and can suppress effector T cell
responses in a by-stander manner through the secretion
of down-regulatory cytokines (Fig. 1).
However, as mentioned above the protective function
of Treg against severe gastritis in H. pylori infection is
not achieved without costs. As shown in our mouse
studies [34], the protective effect of Treg against gastritis
was associated with more extensive bacterial colonization. Evidence from H. pylori infected patients developing duodenal ulcers suggests, that the ulcers develop in
the apparent presence of increased numbers of mucosal
Fig. 1. Proposed role of Treg in the regulation of H. pylori induced inflammation in the gastric mucosa. Upon infection with H. pylori bacteria, the
epithelial barrier is compromised due to the vacuolating effects of cytotoxin VacA, with consequent leakage of antigens into the gastric lumen. Tissue
resident dendritic cells or macrophages take up and present H. pylori antigen while at the same time they may also under inflammatory conditions
present self-antigens. (a) H. pylori specific T cells primed by their by their specific antigen in the local lymph node home to the stomach and
proliferate in response to H. pylori antigens presented by activated APCs. Proliferating H. pylori specific CD4+ T cells secrete proinflammatory
cytokines, such as IFN-c, TNF-a and IL-2. (b) Self-antigen specific Treg prevent T cell reactivity to self, either by down regulating APC function or
through direct cell contact with T cells in the gastric mucosa. (c) Treg recognizing H. pylori antigens regulate the potentially pathogenic and
inflammatory Th1 T cells that have infiltrated the gastric mucosa during infection with H. pylori. Thus Treg function as immunological check points,
exemplified by the fact that they are important in the control of both potentially self reactive and H. pylori specific T cells, during an active chronic
inflammation as a result of H. pylori infection.
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Treg and increased production of anti-inflammatory
cytokines IL-10 and TGF-b in the duodenal epithelium
[41,42]. In addition, the findings of increased numbers of
H. pylori bacteria in duodenal biopsies of patients with
duodenal ulcers compared to asymptomatic carriers
[43] suggests that Treg in the duodenal mucosa may contribute to pathology by allowing more extensive local
colonization of H. pylori bacteria which cause tissue
damage by producing vacuolating cytotoxin and possibly other virulence factors. At the same time Treg in
the gastric mucosa are important in the protection
against symptomatic gastric inflammation and perhaps
even progression to cancer.
5. Concluding remarks
The studies summarized above point to an equally
important role for Treg in the down-regulation of immune responses to infection as has previously been
shown for maintenance of self-tolerance and prevention
of autoimmunity. Ideally, during an infection Treg
could modulate the delicate balance between the need
to mount an immune response that can effectively control the pathogen and the associated risk of a too vigorous immune response that would cause severe
inflammation and disease. Expansion of the number of
Treg or enhancement of their function may inhibit tissue
damaging inflammation but at the cost of increasing the
load of infection, and conversely their removal or inhibition may enhance host resistance to the infection.
Potentially, vaccines against infectious diseases may
be designed to steer pathogen-specific Treg in the desired direction. Most, if not all infections trigger some
extent of inflammation, as does efficient vaccination
against pathogens. However, infection with H. pylori
represents a situation where the balance between beneficial and harmful effects of the immune response seems
particularly complex, including the possible role of
Treg at different locations. This could have obvious
bearing on the prospects for vaccine development
against H. pylori, especially when a vaccine for use in
infected individuals is being considered, and will require
further studies in both experimental systems and in humans with natural H. pylori infection. Will it for instance be possible to design a vaccine that combines
the ability to raise a strong protective immune response
to a specific H. pylori antigen while at the same time
expanding the number of Treg and/or inducing other
regulatory T cells against different H. pylori antigens?
And would such a combined T effector/Treg-inducing
vaccine provide the desired result of increased pathogen
elimination together with prevention of tissue damage?
Whilst there are still many unanswered questions
regarding the mechanism of suppression and antigen
specificity, their potential as therapeutic targets in
inflammatory diseases should encourage efforts to further characterize these cells.
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