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Immune Regulation in the Intestine

A Balancing Act between Effector and


Regulatory T Cell Responses
FIONA POWRIE
Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom

ABSTRACT: The immune system in the intestine must respond rapidly to invad-
ing pathogens without mounting sustained effector cell responses to the indig-
enous commensal bacteria. Results from this laboratory using the T cell
transfer model of colitis suggest that specialized populations of regulatory T
cells control the immune response in the intestine. Regulatory T (Tr) cell activ-
ity is enriched within the naturally arising CD4 CD25 Tr subset that has
been shown to prevent a number of inflammatory diseases. CD4 CD25 Tr
cells control intestinal inflammation induced by both innate and adaptive
immune responses via IL-10– and TGF-–dependent mechanisms. Recent
results have shown that CD4 CD25 Tr cells can cure established colitis,
suggesting their utility for the treatment of inflammatory bowel disease.

KEYWORDS: regulatory T cell; inflammatory bowel disease; colitis; T cell


transfer; IL-10; TGF-

INTRODUCTION

The gastrointestinal (GI) tract is the largest interface between the immune system
and the outside world. It is home to a large number and diverse array of commensal
bacteria and is also one of the major surfaces through which pathogens gain access
to the body. Immune cells in the intestine are intimately associated with the epithe-
lium and are continually challenged by a myriad of antigens derived from food and
commensal bacteria, as well as pathogenic organisms. Specific anatomical features
of the intestine and the presence of specialized immune cells ensures rapid and local
responses to contain and eradicate pathogens without development of sustained
inflammatory responses to harmless intestinal antigens.1
The intestinal bacterial complex, composed of over 400 species in humans, exists
in an overall symbiotic relationship with the host, playing an important role in nutri-
tion, host defense, and organ development.2 Although the majority of commensal
bacteria are separated from immune cells by the epithelial cell barrier, there is good

Address for correspondence: Fiona Powrie, Sir William Dunn School of Pathology, University
of Oxford, South Parks Road, Oxford OX1 3RE, UK. Fax: +44-1865-275591.
fiona.powrie@path.ox.ac.uk

Ann. N.Y. Acad. Sci. 1029: 132–141 (2004). © 2004 New York Academy of Sciences.
doi: 10.1196/annals.1309.030

132
POWRIE: IMMUNE REGULATION IN THE INTESTINE 133

evidence that local immune responses are activated in response to intestinal bacte-
ria.3,4 Production of anti-inflammatory cytokines, such as IL-10 and TGF-β, is often
dominant during immune responses at mucosal surfaces, and this may be an impor-
tant adaptive mechanism to prevent the development of chronic inflammation.1
Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and
ulcerative colitis, is a chronic condition involving relapsing and remitting inflamma-
tion of the gastrointestinal tract.5 Clinical and experimental studies suggest that IBD
is the consequence of an aberrant inflammatory response to intestinal bacteria that
occurs in genetically susceptible individuals.6 Recently, mutations in the intracellu-
lar bacterial sensing protein, nucleotide-binding oligomerization domain 2 (NOD2),
have been shown to confer susceptibility to CD.7,8 Although it is not fully under-
stood how alterations in the NOD2 bacterial recognition pathway predispose to IBD,
the results do identify innate immune recognition pathways as important in control-
ling intestinal inflammation.
The complex multifactorial nature of IBD makes it difficult to dissect the role of
individual components in the etiology and pathogenesis of disease. Over the last
decade, a number of models of chronic intestinal inflammation have been described
that share features with human IBD (reviewed in Ref. 6). Results from these studies
have shown that IBD can develop as a consequence of altered intestinal barrier func-
tion, impaired innate immunity, excessive effector cell responses, or a deficiency in
regulatory pathways.
Studies from this laboratory using the T cell transfer model of colitis indicate that
CD4+ regulatory T cells (Tr) play a key role in intestinal homeostasis. Here, we
describe the properties of Tr cells that control intestinal inflammation and discuss
their application for therapy in IBD.

T CELL TRANSFER MODEL OF COLITIS

In mice, transfer of primarily naive (CD45RBhigh) CD4+ T cells to T and B cell–


deficient recipients leads to wasting disease and colitis.10,11 Intestinal inflamma-
tion resembles that seen in human IBD, with transmural leukocytic infiltrates, epi-
thelial cell hyperplasia, and goblet cell depletion. Immune pathology in this model
is Th1-mediated and, accordingly, can be prevented by treatment with antibodies to
IL-12p40, TNFα, or IFNγ.12,13 As with other models, colitis is bacterially driven,
as it does not occur when T cells are transferred to recipients that have been main-
tained in germ-free conditions, or that have reduced bacterial loads.14,15 Colitis in
the T cell transfer model has not been attributed to the presence of a common patho-
gen, and it seems more likely that commensal bacteria stimulate the inflammatory
response. T cells reactive to antigens from the normal bacterial flora are present in
mice and humans with IBD,16 providing clear evidence that development of intesti-
nal inflammation is accompanied by immune sensitization toward the commensal
flora. Monocolonization of germ-free SCID mice with Helicobacter muridarium
results in colitis following transfer of CD4+ CD45RBhigh cells, indicating that a
single commensal bacterial species is sufficient to induce T cell–mediated colitis.17
134 ANNALS NEW YORK ACADEMY OF SCIENCES

ACTIVATED DENDRITIC CELLS DRIVE


INTESTINAL INFLAMMATION

Dendritic cells (DCs) are abundant in the GI tract, in organized lymphoid struc-
tures, as well as in the lamina propria, where they may sample incoming antigens.
DCs express a number of pattern recognition receptors on their surface, allowing
them to detect and respond to the presence of microbes.18 Bacteria-induced activa-
tion of DCs leads to their maturation and migration to the secondary lymphoid
organs, where they are able to present antigen to naive T cells. In addition, mature,
activated DCs produce a number of inflammatory cytokines and costimulatory
molecules that are required for the development of sustained T cell responses.
In mice with colitis there is an accumulation of DCs in the mesenteric lymph
nodes (MLNs) as well as in colonic LP.19,20 DCs in the MLNs expressed an activated
phenotype with increased expression of CD40 and the TNF-like molecule CD134L.
Analysis of T cell proliferation in mice with colitis showed that up to 20 to 30% of
T cells were proliferating in the MLNs, consistent with the high proportion of acti-
vated DCs present.21 Activated T cells express the cell surface costimulatory mole-
cules CD40 ligand (CD40L) and CD134. CD40L binds CD40 on antigen-presenting
cells (APCs), inducing CD134L expression22 leading to the transmission of further
activatory signals to both the T cell and APC. The CD40-CD40L and CD134L-
CD134 pathways play functional roles in the inflammatory response, as blockade of
either pathway inhibits colitis.19,23,24
In addition to proliferating in the draining lymph nodes, colitogenic T cells also
proliferated locally in the colon. Proliferating T cells were typically located adjacent
to DCs in organized leukocyte clusters in the lamina propria.21 T cells were found
to home to DC clusters in the colon very early after transfer into immune-deficient
recipients, prior to the onset of colitis,20 making it tempting to speculate that colonic
leukocyte clusters also contribute to the initiation and perpetuation of the inflamma-
tory response in the intestine.
Together, the data suggest that interactions between activated DCs and activated
T cells drive intestinal inflammation, and that disruption of this positive-feedback
loop is sufficient to inhibit colitis.

COLITIS AS A RESULT OF SUSTAINED ACTIVATION


OF THE INNATE IMMUNE SYSTEM

The activation of the innate immune system that accompanies T cell–dependent


colitis suggests a causative link between innate effector mechanisms and intestinal
pathology. Infection with the mouse intestinal pathogen Helicobacter hepaticus
triggers typholocolitis in several strains of immune-deficient mice, providing direct
evidence that chronic colitis can develop in the absence of T cells.25–27 H. hepaticus
infection of 129SvEv RAG-2−/− mice induces systemic and local activation of innate
immune cells, with accumulation of neutrophils, macrophages, and IFNγ-producing
natural killer (NK) cells in the spleen as well as in the intestine.27 Similar to T cell–
dependent colitis, the proinflammatory cytokines IL-12p40 and TNFα play func-
tional roles in the immune pathological response, suggesting that intestinal inflam-
POWRIE: IMMUNE REGULATION IN THE INTESTINE 135

mation involving adaptive or innate immune mechanisms involves common effector


mechanisms.

PREVENTION OF COLITIS BY CD4 CD25 REGULATORY T CELLS

An important theme that has emerged from the T cell transfer model is that func-
tionally specialized Tr cells capable of inhibiting intestinal inflammation are present
among the CD4+ T cell pool in normal mice. Initially identified as being contained
within the antigen-experienced CD4+ CD45RBlow population,11 Tr cell activity has
since been shown to be enriched within the CD4+ CD25+ subset.28 These “naturally
occurring” Tr cells inhibit T cell proliferation in vitro, and are important in the con-
trol of T cell responses to self-antigens, thus preventing the development of autoim-
mune disease.29 Recent studies have shown that CD4+ CD25+ Tr cells also play a
more general suppressive role, acting to limit immune pathology associated with
chronic immune stimulation.30
CD4+ CD25+ Tr cells account for 5 to 10% of peripheral T cells in mice, rats, and
humans.29 A feature that distinguishes CD4+ CD25+ Tr cells from other CD4+ T
cells is that they adopt their effector function in the thymus.29 Current evidence
suggests that CD4+ T cells bearing receptors with a high affinity for self-peptide will
differentiate into CD4+ CD25+ Tr cells following an encounter with cognate peptide
on thymic stromal cells.31 Foxp3, from the family of forkhead/winged helix tran-
scription factors, is differentially expressed by CD4+ CD25+ Tr cells and is required
for their development in the thymus.32,33 Retroviral transduction with Foxp3 leads
to the development of regulatory T cells from naive precursors, indicating that Foxp3
may be a master control switch for Tr cell development.34 Importantly, loss-of-func-
tion mutations in Foxp3 have been shown to be responsible for the lymphoprolifer-
ative disease that develops in scurfy mice, and for the human disease immune
polyendocrine enteropathy X-linked (IPEX) syndrome.35 Strikingly, patients with
IPEX develop a similar spectrum of diseases that develops in animal models in the
absence of regulatory T cells, including type 1 diabetes, allergy, and IBD-like
enteropathy.

CD4 CD25 Tr CELLS SUPPRESS THE INNATE IMMUNE RESPONSE

Transfer of CD4+CD25+ Tr cells prevents the accumulation of activated DCs in


immune-deficient mice transfused with CD4+ CD45RBhigh T cells, suggesting that
Tr cells act to inhibit the ability of DCs to induce a sustained T cell response.19
T cell–independent colitis that develops in 129SvEv RAG2−/− mice following
Helicobacter hepaticus infection can also be inhibited by transfer of CD4+ CD25+
Tr cells, providing direct evidence that CD4+ CD25+ Tr cells suppress the innate
immune response.27,36 Tr cells were found to accumulate in the spleen, MLNs, and
colon, and suppressed local and systemic innate immune pathology via IL-10– and
TGF-β–dependent mechanisms. CD4+ CD25+ Tr cells from IL-10−/− mice failed to
inhibit colitis, suggesting that IL-10 production is crucial for their function. Kinetic
studies showed that the suppressive effects of CD4+ CD25+ Tr cells were most evi-
dent later in infection, suggesting that Tr cells do not inhibit the initial activation of
136 ANNALS NEW YORK ACADEMY OF SCIENCES

the innate immune response but act to prevent chronic activation. Indeed, there is
evidence that stimulation via the toll-like receptor (TLR) pathway breaks Tr-
mediated control by a mechanism involving IL-6 production by activated DCs.37
The ability of CD4+ CD25+ Tr cells to control the innate immune response may
underlie the ability of these cells to inhibit chronic immune responses to a number
of infectious agents, and be an important host mechanism to prevent immune pathol-
ogy during persistent microbial infection.27,38,39

SPECIFICITY

The specificity of CD4+ CD25+ Tr cells that control intestinal inflammation


remains something of an enigma. CD4+ CD25+ Tr cells isolated from mice that had
not been infected with Helicobacter hepaticus were capable of preventing T cell–in-
dependent colitis, indicating that Tr cells can suppress immune pathology triggered
by organisms to which they have not been exposed.27 However, the ability to control
T cell–dependent colitis was enhanced in Tr populations from Helicobacter hepati-
cus–infected donors, suggesting that bacterial infection can induce antigen-specific
Tr cells.40 Furthermore, these bacteria-specific Tr cells were found to be within the
CD4+ CD25− T cell subset. Together, the data are compatible with the view that
CD4+ CD25+ Tr cells able to prevent H. hepaticus–induced colitis occur naturally in
all mice, while a further CD4+ CD25− regulatory population can be primed in the
presence of H. hepaticus infection.

OTHER SUBSETS OF Tr CELLS

In addition to naturally occurring CD4+ CD25+ Tr cells, antigen-induced IL-10–


secreting Tr1 cells also play an important role in intestinal homeostasis. Tr1 cells
inhibit Th1 and Th2 responses via IL-10–dependent mechanisms.41 Tr1 cells devel-
op alongside Th1 cells in a number of chronic infectious diseases and are present in
the intestine of normal mice, where they regulate the response to intestinal
pathogens40 and the commensal flora.42 Recently, pathogen-derived molecules have
been shown to stimulate IL-10 production from DCs via a TLR-4–dependent mech-
anism.43 DC production of IL-10 favors Tr1 cell development, illustrating that, in
addition to inducing proinflammatory responses, microbial-induced activation of the
innate immune system also induces anti-inflammatory cytokines and Tr cell
development.
Although Tr1 cells have some properties similar to those of CD4+ CD25+ Tr cells,
they do not express Foxp3, suggesting that they are a distinct population of cells.9
Studies in vitro have shown that CD4+ CD25+ cells can act on naive T cells to induce
their differentiation to Tr1 cells,44 raising the possibility that CD4+ CD25+ Tr and
Tr1 cells synergize to control inflammation.

THE ROLE OF IMMUNE SUPPRESSIVE CYTOKINES IN Tr FUNCTION

The immune suppressive cytokines IL-10 and TGF-β play nonredundant roles in
intestinal homeostasis, as IL-10−/−45 and TGF-β1−/−46 mice develop chronic colitis.
POWRIE: IMMUNE REGULATION IN THE INTESTINE 137

Colitis in IL-10−/− mice may be attributable in part to deficient Tr activity, as IL-10


production by Tr cells has been shown to be essential for control of intestinal inflam-
mation.27,40,47 IL-10 mediates a wide range of suppressive activities on T cells, as
well as innate immune cells such as myeloid cells and neutrophils.48 Suppression of
intestinal inflammation by IL-10 may be mediated primarily via effects on innate
immune cells, as disruption of IL-10 signaling in myeloid cells and neutrophils, but
not T cells, triggered colitis.49
Suppression of T cell–dependent and T cell–independent colitis by CD4+ CD25+
Tr cells was abrogated by anti–TGF-β treatment.14,27 By contrast with IL-10, the
effects of TGF-β may be mediated primarily via negative regulation of T cells, as
mice expressing a dominant negative form of the TGF-βRII (dnTGF-βRII) restricted
to T cells developed an IBD-like syndrome.50 Recently, we have found that colitis
induced by transfer of CD4+ CD45RBhigh cells isolated from dnTGF-βRII transgen-
ic mice cannot be suppressed by CD4+ CD25+ Tr cells, indicating that T cells that
cannot respond to TGF-β escape control by Tr cells (S. Read, L. Fahlen, and F. Pow-
rie, unpublished data). Recent studies indicate that TGF-β can also act as a costim-
ulatory molecule for development of Foxp3+ Tr cells from naive precursors,
suggesting that TGF-β may also be involved in the generation of Tr cells.51
There are conflicting data on whether production of TGF-β by CD4+ CD25+ Tr
cells is required for their function.52,53 CD4+ CD25+ Tr cells express membrane
bound TGF-β,52 and the ability of CD4+ Tr populations to suppress colitis was found
to correlate with expression of membrane-bound TGF-β or latency-associated
peptide.54,55 In addition, CD4+ CD25+ cells from TGF-β1−/− mice failed to prevent
colitis in the T cell transfer model,54 further supporting a role for TGF-β1 production
by Tr cells themselves. However, in our own studies we have found that TGF-β1−/−
CD4+ CD25+ Tr cells retain the ability to suppress colitis. Addition of anti–TGF-β
monoclonal antibody abrogates suppression of colitis by TGF-β1−/− CD4+ CD25+ Tr
cells, indicating that in some settings TGF-β from non–Tr-derived sources is suffi-
cient to control the inflammatory response (Fahlen, Read, and Powrie, unpublished
data).

CURE OF COLITIS BY CD4 CD25 Tr CELLS

The ability of various populations of Tr cells to prevent development of experi-


mental colitis suggests that stimulation of these cells may be beneficial in patients
with IBD. However, to be of use in the clinical setting, Tr cells must be able to inhibit
ongoing T cell responses and reverse established pathology. In recent studies we
found that a single transfusion of CD4+ CD25+ Tr cells into mice with established
colitis led to resolution of the inflammatory response and restoration of normal
intestinal architecture.21 Others found similar results and showed, furthermore, that
the therapeutic effect of CD4+ CD25+ Tr cells is mediated via IL-10 and TGF-β.56
A characteristic feature of CD4+ CD25+ Tr cells is their inability to undergo
mitogen- or antigen-induced proliferation in vitro.29 By contrast, after transfer into
colitic mice, Tr cells were found to proliferate in MLN and colon, where they inhib-
ited the proliferation of pathogenic CD4+ T cells.21 The presence of regulatory T
cells in the colon was also associated with cure of colitis by Tr1 cells,57 suggesting
that suppression of established inflammation requires Tr activity in secondary lym-
138 ANNALS NEW YORK ACADEMY OF SCIENCES

phoid tissue and effector sites. Recently, a subset of CD4+ CD25+ Tr cells expressing
the integrin αE (CD103) was shown to home most efficiently to inflammatory sites
and to control acute inflammation. This suggests that distinct subsets of Tr cells may
control responses in lymphoid organs and tissues.58 Proliferation of CD4+ CD25+ Tr
cells was significantly reduced following resolution of the inflammatory response,
suggesting that CD4+ CD25+ Tr cells respond to the inflammation that they
regulate.21
In the MLN and colon, CD4+ CD25+ Tr cells localized at the interface between
pathogenic effector T cells and DCs and were in direct contact with both populations
of cells.21 This specific distribution in vivo may reflect the ability of activated DCs
to induce the activation and migration of CD4+ CD25+ Tr cells.59,60 Tr cells, in turn,
may suppress the immune response via effects on activated DCs1 or via direct effects
on effector T cells.62

OUTLOOK

The balance between effector and regulatory T cell responses is a key factor in
the development of intestinal inflammation. There is now a large body of evidence
showing that enhancement of Tr cell activity can prevent and even cure intestinal
inflammation in mouse models, suggesting novel therapeutic strategies for the treat-
ment of IBD. IPEX patients lacking functional Foxp3 protein develop severe enter-
opathy, suggesting that Tr cells also control intestinal inflammation in humans.
However, further studies are required to determine whether defects in Tr activity are
associated with genetic susceptibility to IBD in humans.

ACKNOWLEDGMENTS

F. Powrie is funded by the Wellcome Trust.

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