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ISBN: 978-0-12-803415-6
ISSN: 1877-1173
Jakub Abramson
Faculty of Biology, Department of Immunology, Weizmann Institute of Science, Rehovot,
Israel
Michael Delacher
Immune Tolerance, Tumor Immunology Program, German Cancer Research Center
(DKFZ), Heidelberg, Germany
Maxime Dhainaut
Laboratory of Immunobiology, Department of Molecular Biology, Université Libre de
Bruxelles, Brussel, Belgium
Darcy Ellis
Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department
of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
Markus Feuerer
Immune Tolerance, Tumor Immunology Program, German Cancer Research Center
(DKFZ), Heidelberg, Germany
Thomas S. Fulford
Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department
of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
Steve Gerondakis
Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department
of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
Yael Goldfarb
Faculty of Biology, Department of Immunology, Weizmann Institute of Science, Rehovot,
Israel
Ann-Cathrin Hofer
Immune Tolerance, Tumor Immunology Program, German Cancer Research Center
(DKFZ), Heidelberg, Germany
Jochen Huehn
Department of Experimental Immunology, Helmholtz Centre for Infection Research,
Braunschweig, Germany
Axel Kallies
Walter and Eliza Hall Institute of Medical Research, and Department of Medical Biology,
University of Melbourne, Parkville, Victoria, Australia
Danny Kägebein
Immune Tolerance, Tumor Immunology Program, German Cancer Research Center
(DKFZ), Heidelberg, Germany
ix
x Contributors
Yohko Kitagawa
Department of Experimental Immunology, Immunology Frontier Research Center, Osaka
University, Suita, Osaka, Japan
Noriko Komatsu
Department of Immunology, Graduate School of Medicine and Faculty of Medicine,
The University of Tokyo, Bunkyo-ku, Tokyo, Japan
Adrian Liston
Translational Immunology Laboratory, VIB, and Department of Microbiology and
Immunology, University of Leuven, Leuven, Belgium
Matthias Lochner
Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical
Infection Research: A Joint Venture Between the Medical School Hannover (MHH) and the
Helmholtz Centre for Infection Research (HZI), Hannover, Germany
Jennifer M. Lund
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, and
Department of Global Health, University of Washington, Seattle, Washington, USA
Muriel Moser
Laboratory of Immunobiology, Department of Molecular Biology, Université Libre de
Bruxelles, Brussel, Belgium
Vitalijs Ovcinnikovs
Institute of Immunity & Transplantation, Division of Infection & Immunity, University
College London, London, United Kingdom
Maria Pasztoi
Department of Experimental Immunology, Helmholtz Centre for Infection Research,
Braunschweig, Germany
Joern Pezoldt
Department of Experimental Immunology, Helmholtz Centre for Infection Research,
Braunschweig, Germany
David M. Richards
Immune Tolerance, Tumor Immunology Program, German Cancer Research Center
(DKFZ), Heidelberg, Germany
Laura E. Richert-Spuhler
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle,
Washington, USA
Shimon Sakaguchi
Department of Experimental Immunology, Immunology Frontier Research Center, Osaka
University, Suita, Osaka, Japan
Tim Sparwasser
Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical
Infection Research: A Joint Venture Between the Medical School Hannover (MHH) and the
Helmholtz Centre for Infection Research (HZI), Hannover, Germany
Contributors xi
Hiroshi Takayanagi
Department of Immunology, Graduate School of Medicine and Faculty of Medicine,
The University of Tokyo, and Japan Science and Technology Agency, Exploratory Research
for Advanced Technology Program, Takayanagi Osteonetwork Project, Bunkyo-ku,
Tokyo, Japan
Peggy P. Teh
Walter and Eliza Hall Institute of Medical Research, and Department of Medical Biology,
University of Melbourne, Parkville, Victoria, Australia
Annemarie van Nieuwenhuijze
Translational Immunology Laboratory, VIB, and Department of Microbiology and
Immunology, University of Leuven, Leuven, Belgium
Ajithkumar Vasanthakumar
Walter and Eliza Hall Institute of Medical Research, and Department of Medical Biology,
University of Melbourne, Parkville, Victoria, Australia
Lucy S.K. Walker
Institute of Immunity & Transplantation, Division of Infection & Immunity, University
College London, London, United Kingdom
Zuobai Wang
Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical
Infection Research: A Joint Venture Between the Medical School Hannover (MHH) and the
Helmholtz Centre for Infection Research (HZI), Hannover, Germany
James Badger Wing
Department of Experimental Immunology, Immunology Frontier Research Center, Osaka
University, Suita, Osaka, Japan
PREFACE
Regulatory T cells (or Tregs) are a unique subpopulation of T cells with sup-
pressive properties, acting to counter the immunogenic function of other
T cells. This function is critical for the prevention of autoimmune disease
and also has profound impacts on other aspects of the mammalian immune
system, leading to an intensive effort to harness the power of Tregs as a novel
therapeutic strategy across multiple immune diseases.
This volume takes a broad and comprehensive look at Tregs in health
and disease states. We have expert chapters on the generation of Tregs, with
contributions by Sakaguchi, Huehn, Feuerer, and Abramson on the pro-
cesses by which Tregs are generated in the thymus and peripheral organs
such as the gut. Complementing these chapters, we have articles by Geron-
dakis, van Nieuwenhuijze, and Kallies, which dissect the molecular path-
ways that control the induction and differentiation of Tregs. Sparwasser
and Moser discuss the cellular dynamics Tregs share with Th17 cells and
dendritic cells. Finally, we have an assessment of the physiological impact
on Tregs in disease, with expert chapters by Takayanagi, Lund, and Walker
on the role of Tregs in arthritis, infection, and diabetes.
ADRIAN LISTON
xiii
CHAPTER ONE
Contents
1. Introduction 2
2. Transcriptional Regulation in Treg Cells 4
2.1 Foxp3-Dependent Transcriptional Regulation 4
2.2 Foxp3-Independent Transcriptional Regulation 9
3. Epigenetic Regulation in Treg Cells 10
3.1 Stability of the Treg Cell Lineage 10
3.2 cis-Regulatory Elements of the Foxp3 Gene 12
3.3 DNA Demethylation 13
3.4 Histone Modification 14
3.5 Nucleosome Positioning 16
4. Cross talk Between Foxp3-Dependent Gene Regulation and Treg Cell-Type
Epigenetic Modifications 17
5. Treg Cell Development 18
5.1 Signals Involved in Treg Cell Development 20
5.2 Transcription Factors Involved in Foxp3 Induction 21
5.3 Induction of Epigenetic Modification During Treg Cell Development 24
5.4 Coordination of Transcriptional and Epigenetic Changes During Treg Cell
Development 25
6. Conclusion 27
Acknowledgment 27
References 27
Abstract
The control of immune responses against self and nonharmful environmental antigens
is of critical importance to the immune homeostasis. Regulatory T (Treg) cells are the key
players of such immune regulation and their deficiency and dysfunction are associated
with various immune disorders, such as autoimmunity and allergy. It is therefore essen-
tial to understand the molecular mechanisms that make up Treg cell characteristics; that
is, how their unique gene expression profile is regulated at transcriptional and
Progress in Molecular Biology and Translational Science, Volume 136 # 2015 Elsevier Inc. 1
ISSN 1877-1173 All rights reserved.
http://dx.doi.org/10.1016/bs.pmbts.2015.07.011
2 Yohko Kitagawa et al.
1. INTRODUCTION
Treg cells are a subset of CD4+ T cells, specialized in the maintenance
of immune tolerance and prevention of autoimmunity. Treg cells are unique
in that their primary function is to suppress aberrant or excessive immune
responses harmful to the host by counteracting the effects of conventional
T cells. This property of Treg cells is particularly important in the establish-
ment of self-tolerance. Discrimination between self and nonself is required
for the immune system to avoid attacking self-tissues and organs and causing
autoimmune diseases. Along with deletion of self-reactive T cells during
their development and induction of an anergic state in self-reactive
T cells in peripheral lymphoid organs, thymic production of Treg cells,
and their immune suppression in the periphery are a critical mechanism
of self-tolerance. In addition, conventional T cells can give rise to Treg cells
under certain conditions, contributing to immune homeostasis in the
periphery.
The production of suppressive cells in the thymus was initially noted in
experiments where the removal of thymus from neonatal mice led to severe
autoimmunity.1 However, it was not until 1995 that Treg cells were defin-
itively identified by specific expression of the alpha chain of the IL-2 recep-
tor (CD25),2 which enabled the finding that Treg cells constituted around
10% of CD4+ T cells and clearly demonstrating that they have a critical role
in self-tolerance. This was then further confirmed with the discovery of the
lineage defining transcription factor Foxp3.3,4 Foxp3 is essential for the
function of Treg cells, as loss-of-function mutations of Foxp3 in either
the scurfy mouse strain or IPEX (immunodysregulation, poly-
endocrinopathy, enteropathy, X-linked) syndrome leads to severe autoim-
munity including Type-1 diabetes (T1D), immunopathology such as
inflammatory bowel disease, and allergy accompanying hyperproduction
of IgE.5–7 Furthermore, depletion of Treg cells in adults also leads to similar
autoimmune pathology, demonstrating that Treg cells are needed not just
for the establishment, but also the lifelong maintenance, of immune self-
tolerance and homeostasis.8
In addition to severe acute autoimmunity seen in the complete absence
of Treg cells, more subtle defects in Treg cell function have been implicated
Transcriptional and Epigenetic Control 3
high-affinity IL-2 receptor even at the resting state gives Treg cells an advan-
tage and IL-2 deprivation by Treg cells from other T cells is one mechanism
of immune suppression. Indeed, overexpression of CTLA4 and repression of
IL-2 in conventional T cells enable them to behave like Treg cells.21 Con-
versely, failure to repress IL-2 in Treg cells is associated with the develop-
ment of autoimmunity.22
These molecular features are regulated at both the transcriptional and epi-
genetic levels. Foxp3-dependent transcriptional programs, which often
involve interaction with other transcription factors, control some Treg cell-
type gene expression, while Foxp3-independent epigenetic modifications also
contribute to the generation of Treg cell characteristics. There is dynamic
cross talk between transcriptional and epigenetic regulation in a cooperative
manner, which enables stable maintenance of Treg cell characteristics
throughout multiple divisions, regardless of environmental changes. Given
the critical and wide-ranging roles of Treg cells in autoimmunity, allergy,
infection, and tumor immunology, it is vital to understand the molecular
mechanisms underlying the development and maintenance of Treg cells in
order to develop more sophisticated strategies to either enhance or dampen
the function of Treg cells in clinical settings. Here, we review the current
understanding of transcriptional and epigenetic regulation in Treg cells and
discuss how these molecular changes occur during Treg cell development.
others being T cell or Treg cell-specific ones. Some of the proteins currently
reported to be capable of interacting with Foxp3 are NFκB,32 NFAT,22
Runx1,28 Eos, CtBP1,33 CBFb, Gata3, Ash2l, Bcl11b, Ikzf3, Foxp1,
Smarcc1, Smarce1, Smarca4, Smarca5, Chd4, Hdac2, Rcor1, Lsd1,34
HIF-1α, IRF-4,35 p300, TIP60,36 and Ezh2.26 Though Foxp3 is likely to
exist in a large protein complex, not all these cofactors are always found
in the same complex. There are two features determined by the interaction
with particular cofactors: effects of binding on target gene transcription and
location of Foxp3 binding.
First, Foxp3 can serve as both transcriptional activator and repressor and
these modes of action are determined by the recruitment of coactivators or
corepressors. For example, human FOXP3 protein is capable of interacting
with the coactivators p300 and TIP60 and such interaction promotes the
transcriptional activity of FOXP3, while Treg cell-specific deletion of
p300 and TIP60 results in loss of Treg function.36 In contrast, Foxp3 recruits
Eos and the corepressor CtBP1 to repress the expression of genes such as Il2.
Since IL-2 repression is critical for Treg cell-mediated immune regulation,
silencing Eos in Treg cells abrogates their suppressive function.33 Notably,
some of the factors that Foxp3 interacts with, such as Smarca4, Hdac2, and
Ezh2 are known as epigenetic regulators, suggesting that Foxp3 recruits
these factors to modulate epigenetic features for long-term control of gene
expression (discussed in Section 4). Thus, Foxp3 interacts with appropriate
cofactors in a locus-specific manner in order to generate Treg cell-type gene
expression (Fig. 1).
Second, Foxp3 is dependent on other transcription factors for binding
guidance in some loci, meaning that cofactors alter the targets of its gene
regulation. Some interactions are fundamentally required for generating
Treg cell phenotypes in physiological conditions. For example, NFκB
and NFAT transcription factors have been shown to interact with Foxp3
and cooperatively repress the expression of proinflammatory cytokine genes
such as Il2, Il4, and Ifng.22,32 Mutations at the interface of Foxp3 and NFAT
interaction resulted in the production of IL-2 by Treg cells and failure to
prevent the manifestation of type I diabetes.22 Other interactions are utilized
for particular purposes, such as regulation of specific effector T cell subsets
during inflammation. For example, during Th2-type inflammation, Foxp3
interacts with IRF4, which is a transcription factor essential for Th2 cell dif-
ferentiation program, and enables Treg cells to efficiently control Th2-type
inflammation.37 Importantly, in addition to the variety of Foxp3 complexes
at different genomic loci, the repertoire of Foxp3–cofactor complexes
Transcriptional and Epigenetic Control 7
within a cell may vary depending on the differentiation stage of Treg cells
and the environmental conditions they are exposed to. In this sense, the bal-
ance among Foxp3 cofactors may be an important determinant of what
Foxp3 interacts with. When a fluorescent marker is fused to the
N-terminus of Foxp3, it impaired the interaction of Foxp3 with HIF-1α
and instead recruited IRF4.35 Consequently, some gene regulation is altered
with particular upregulation of IRF4 signature genes, and these mutant Treg
cells alleviated rheumatoid arthritis, but exacerbated type I diabetes.35 The
cause of cofactor change may be due to the competition between HIF-1α
and IRF4, or due to the alteration in posttranslational modification of
Foxp3. Nevertheless, selection of partners for Foxp3 can serve as a molecular
switch for Foxp3-dependent transcription and consequent Treg cell
function.
8 Yohko Kitagawa et al.
Treg cells. For example, Foxo1, which is highly expressed and activated by
phosphorylation in Treg cells, controls a subset of Treg cell-type gene
expression, independently of Foxp3.49 Others, such as Eos and Helios,
are associated with Treg cell-type epigenetic modifications. This suggests
that the permissive chromatin status of these genes enables constitutively
expressed transcription factors to induce their expression, rather than specif-
ically expressed transcription factors being responsible for their expression.48
There are some Foxp3+ T cells that are not committed to Treg cell lin-
eage. TCR stimulation induces Foxp3 expression in some murine conven-
tional T cells and these activation-induced Foxp3+ T cells do not possess
Treg cell characteristics except low expression of Foxp3.54 In humans,
Foxp3 is more loosely regulated and can be transiently upregulated by
in vitro stimulation of CD4+CD25 non-Treg cells, while there is a clear
fraction of Foxp3+ T cells with no suppressive function in vivo.55,56 Foxp3
expression can also be induced in vitro by stimulating both murine and
human conventional T cells in the presence of TGFβ and IL-2.57 These cells
have some suppressive function but are unable to maintain prolonged Foxp3
expression upon removal of such stimulation, indicating that they are not
fully committed to Treg cell lineage. Therefore, maintaining Foxp3 expres-
sion involves additional mechanisms to those that activate Foxp3 promoter
activity. This suggests that whatever that ensures the stable expression of
Foxp3 is the true indicator of Treg cell lineage.
TSDR demethylation is observed at Ikzf4 and Ikzf2 gene loci and these
genes are not upregulated by Foxp3, TCR stimulation, or TGFβ signal-
ing.23,48 With no signals or transcription factors identified to induce and
maintain these genes in Treg cells, it is conceivable that TSDR demethyla-
tion, followed by binding of constitutively expressed transcription factors
induces the expression of some Foxp3-independent genes. Second, TSDR
demethylation is also observed at genes upregulated by Foxp3 and TCR
stimulation, such as Ctla4 and Tnfrsf18.48 This may explain how Treg cells
maintain high level of these molecules, even at a resting state. Taken together,
these findings suggest that TSDR demethylation facilitates Foxp3-dependent
transcriptional regulation by stabilizing Foxp3 expression as well as assisting
with both Foxp3-dependent and -independent gene regulation.
Figure 4 Cross talk between transcriptional and epigenetic regulation for the genera-
tion of Treg cell-type gene expression. Foxp3 expression is induced and maintained by
both transcription factors and epigenetic modifications. Foxp3 then generates some
Treg cell-type gene expression, which includes the upregulation of Foxp3 cofactors.
There are also genes expressed independently of Foxp3, but associated with Treg
cell-specific epigenetic modifications. Some of these genes are further upregulated
by Foxp3, and serve as Foxp3 cofactors. Foxp3 and its cofactors then cooperatively reg-
ulate more gene expression.
Treg cells are broadly divided into two subpopulations, based on their
site of origin. The majority develops in the thymus and is referred to as
thymus-derived Treg (tTreg) cells, while some Treg cells also differentiate
from conventional CD4+ T cells in the peripheral lymphoid organs as
peripherally induced Treg (pTreg) cells (Fig. 5). tTreg cells, particularly
those that develop during neonatal period, are nonredundantly required
for the establishment of self-tolerance.72 In contrast, pTreg cells are predom-
inantly found in mucosa-associated lymphoid tissues such as Peyers’ patches
and lamina propria of small and large intestines, and are involved in the
induction of immune tolerance to commensal microbes and nonpathogenic
environmental antigens, such as food antigens. Moreover, pTreg cells,
which exist only in placental mammals, appear to play roles in the establish-
ment of maternal–fetal tolerance.73 Therefore, tTreg and pTreg cells have a
division of labor in some scenarios. However, in terms of their