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Cellular & Molecular Immunology (2010) 7, 414–418
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REVIEW
Antigen-non-specific regulation centered on
CD251Foxp31 Treg cells
Gangzheng Hu1,2, Zhongmin Liu3, Changqing Zheng2 and Song Guo Zheng4
CD41CD251Foxp31 regulatory T cells (Tregs) are of special interest in immunology because of their potent inhibitory function. Many
fundamental aspects of Tregs, including their antigenic profile, development and peripheral homeostasis, remain highly controversial.
Here, we propose a Treg-centered antigen-non-specific immunoregulation model focused on the T-cell system, particularly on CD41 T
cells. The T-cell pool consists of naive T cells (Tnais), Tregs and effector T cells (Teffs). Regardless of antigen specificity, the ratio of the
activated T-cell subsets (Treg/Teff/Tnai) and their temporal and spatial uniformity dictate the differentiation of Tnais. Activated Tregs
inhibit the activation, proliferation, induction and activity of Teffs; in contrast, activated Teffs inhibit the induction of Tregs from Tnais
but cooperate with Treg-specific antigens to promote the proliferation and activity of Tregs. In many cases, these interactions are
antigen-non-specific, whereas the activation of both Tregs and Teffs is antigen-specific. Memory T-cell subsets are essential for the
maintenance of adaptive immune responses, but the antigen-non-specific interactions among T-cell subsets may be more important
during the establishment of the adaptive immune system to a newly encountered antigen. This is especially important when new and
memory antigens are presented closely—both temporally and spatially—to T cells, because there are always baseline levels of activated
Tregs, which are usually higher than levels of memory T cells for new antigens. Based on this hypothesis, we further infer that, under
physiological conditions, Tregs in lymph nodes mainly recognize antigens frequently released from draining tissues, and that these
self-reactive Tregs are commonly involved in the establishment of adaptive immunity to new antigens and in the feedback control of
excessive responses to pathogens.
Cellular & Molecular Immunology (2010) 7, 414–418; doi:10.1038/cmi.2010.39; published online 23 August 2010
Keywords: antigen; immune regulation; tolerance; Treg
INTRODUCTION
Naive T cells (Tnais) can differentiate into a number of memory T-cell
subsets that are roughly defined as effector T cells (Teffs) and regulatory T cells (Tregs). Th1, Th2, Th9, T follicular helper (Thf) and Th17
are typical Teffs, and CD41CD251Foxp31 T cells are the most
important of the Tregs.1,2 Although mutually inhibitory, both Tregs
and Teffs can be stimulated in an autocrine fashion. This mutually
exclusive induction and antigen-specific recognition is the basis of the
adaptive immune response. Antigen-specific regulation provides a
clear explanation of why memory status is resistant to conversion after
it has been established. Antigen-specific memory T-cell subsets are
activated primarily by subsequent invasion of pathogens and maintain
memory status by facilitating the induction of Tnais into the appropriate T-cell subsets. However, antigen-specific regulation may play
only a small role in the primary establishment of memory status. In
addition, it is difficult to explain how the immune system controls
the balance between mounting a response to pathogens and avoiding
self-destruction by the antigen-specific model. Tregs are capable of
not only maintaining self-tolerance but also inhibiting both adaptive
and innate responses to pathogens.3 Although the potent inhibitory
activity of Treg has been observed in various disease models, many
fundamental characteristics, such as the antigenic profile, peripheral
tolerance induction and the homeostasis mechanism, are not well
understood. In view of the gaps in the antigen-specific model, we
propose here the Treg-centered antigen-non-specific model. The
two models are logically coherent, and their combination may provide
a better understanding of immunoregulation.
ANTIGEN-NON-SPECIFIC FACILITATION OF TREG
DIFFERENTIATION BY ACTIVATED TREGS
CD41 T cells play a pivotal role in the establishment and maintenance
of the adaptive immune response. In peripheral lymphoid organs,
Tnais can differentiate into functionally different subsets. Each subset
tends to promote self-development and inhibit the differentiation of
1
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School
of Medicine, Shanghai, China; 2Department of Gastroenterology, Shengjing Hospital, China Medical University, Shenyang, China; 3Immune Tolerance and Regulation Center,
Shanghai East Hospital at Tongji Univeristy, Shanghai, China and 4Division of Rheumatology/Immunology, Department of Medicine, Keck School of Medicine, University of
Southern California, Los Angeles, CA, USA
Correspondence: Dr SG Zheng, Division of Rheumatology and Immunology, Keck School of Medicine at University of Southern California, 2011 Zonal Ave. HMR 711, Los Angeles,
CA 90033, USA.
E-mail: [email protected]
Correspondence: Dr ZM Liu, Immune Tolerance Center, Shanghai East Hospital, Tongji University, 150 Jimo Road, Shanghai 200120.
E-mail: [email protected]
Received 25 May 2010; revised 17 June 2010; accepted 18 June 2010
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the other subsets. The competition results in one subset dominating
over the others. Apart from the intracellular status of Tnais, many
milieu factors may be involved in the differentiation. There is no doubt
that properties of antigen-loaded antigen-presenting cells (APCs),
such as the expression patterns of cytokines and costimulation molecules, can directly influence T-cell differentiation. The characteristics of the classical MHC II-restricted antigens and the concomitant non-antigenic components (e.g., endogenous or exogenous
adjuvant, innate immunity-associated molecules and antibodies) and
the capture mode of antigens by APCs (e.g., antigen dose, soluble or
particular antigens, antigens from apoptotic or necrotic cells) may be
the elements that initially determine the functional status of APCs. The
subsequent but even more important factors may develop from activated memory T cells. Subsets of memory T cells may affect Tnai
differentiation through both indirect effects on APCs and direct effects
on Tnais via cytokine release or cell contact. The effects are essential for
adaptive immune memory because of the lack of evidence for the
existence of professional antigen-specific memory APCs. If adaptive
immunity has been established, antigen-specific memory T-cell subsets
are activated primarily by the invading antigens, and the memory
status is maintained by facilitating Tnai induction into the same T-cell
subsets.
Although antigen-specific memory mediated by T cells is central to
the adaptive immune response, antigen-non-specific interaction
among T-cell subsets may also play an important role in two situations. The first is when antigens are encountered for the first time,
when no antigen-specific memory T cells are yet present. The second is
when several antigens are presented closely—both temporally and
spatially—to different T-cell subsets. Hence, we propose the antigen
non-specific model for the induction of Tregs (Figure 1). The key
point of this model is that, regardless of antigen specificity, the component ratio of activated T-cell subsets and their temporal and spatial
uniformity largely determine Tnai differentiation. If activated Tregs
outnumber activated Teffs, Tnais preferentially differentiate into
Tregs,4 and vice versa.5 During an individual’s lifespan, the peripheral
immune system is continually exposed to new endogenous and exogenous antigens. In this setting, there are very few, if any, memory
Tregs and Teffs specific for newly encountered antigens. The number
of activated Tnais is proportional to the dose of the priming antigens.
The number of activated Tregs is determined mainly by the base level
of activated Tregs, as well as by the dose and memory status of the
concomitant antigens, which also determine the number of activated
Teffs. In most cases, newly encountered antigens represent only a
fraction of a complex mix of antigens. The concomitant antigens are
regarded as making up the remaining portion of the mixed antigens,
but they can be presented to the specific memory T-cell subsets.
With respect to tumor cells, newly mutated neo-antigenic peptides
and normal cell components are presented to T cells concurrently. The
Figure 1 Antigen-non-specific control of differentiation of Tnais. Mixed antigens are temporally and spatially closely presented to T-cell subsets in the peripheral lymph
nodes. Regardless of antigen specificity, when activated Tregs outnumber activated Teffs, Tnais preferentially differentiate into Tregs (a), whereas when Teffs
dominate, Tnais preferentially differentiate into Teffs (b). TCR, T-cell receptor; Teff, effector T cell; Tnai, naive T cell; Treg, regulatory T cell.
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low ratio of mutated tumor antigens to normal cell components, and
the preferential recognition of the latter antigens by Tregs, may contribute to the induction of tolerance to tumor cells during the very
early stages of oncogenesis. Chronic infection, especially intracellular
infection, is more favorable than acute infection for the induction of
tolerance because of the decreased level of foreign antigens and the
increased level of antigens resulting from the infected tissues (necrotic
or apoptotic tissue cells). In addition to antigens, cytokines produced
in the tumor and inflammatory milieu determine the fate of Teffs and
Tregs. In acute inflammation, IL-6, tumor-necrosis factor-a and other
proinflammatory cytokines produced by the innate immune system
stimulate immune activity and downregulate Tregs.6 IL-6 also abolishes
the suppressive ability of Tregs in inflammatory conditions.7 Moreover, IL-6 enables natural Tregs to become Th17 cells that may assist
the immune response in early inflammation.8,9 It has been shown that
tumor cells produce large amounts of transforming growth factor-b,
which has an essential role in converting Tnais to Tregs.10–13 In the
late stages of inflammation, transforming growth factor-b becomes
the predominant cytokine and subsequently promotes Treg differentiation and development.
In summary, the ratio of the three kinds of antigen components—
antigens presented to Tregs, Teffs and Tnais—influences Tnai differentiation. The antigen non-specific interplay requires that the different
antigens be presented closely—both temporally and spatially—to the
T-cell subsets. This is seen when various APCs present different antigens in the same lymph node or when one APC captures many types of
antigens.
FORMATION OF THE ANTIGENIC PROFILE OF TREGS IN THE
PERIPHERAL LYMPHOID ORGANS
The antigen-non-specific model of Treg induction provides new
insights into the formation of the antigenic profile of Tregs in the
periphery. The thymus begins to produce naturally occurring Tregs
(nTregs) in the earliest stages of life.14 Self-antigens expressed in the
thymus are involved in the development of these cells.15 Aire is
believed to induce expression of a wide repertoire of peripheral tissue
antigens in medullary epithelial cells, and this expression controls the
clonal selection of thymocytes.16 However, it is possible that Aire does
not control the repertoire of T-cell receptors (TCRs) in Foxp31
Tregs.16,17 Because it is unnecessary for the thymus to express all types
of self-antigens, nTregs might recognize only a representative profile
of self-antigens. The nTregs produced in the first several days after
birth migrate to peripheral lymphoid organs to become the earliest
members of peripheral Tregs. These early nTregs are continuously
activated both by systemic self-antigens coming from the blood and
by local self-antigens coming from the draining tissues. Besides the
Figure 2 Thymus-generated Tregs facilitate the development of peripherally iTregs in an antigen-non-specific manner. Tnais and nTregs, which bear different TCRs,
migrate from the thymus to peripheral lymphoid organs, where certain nTregs are activated, and promote the development of iTregs in an antigen-non-specific
manner. iTreg, induced regulatory T cell; nTreg, naturally occurring regulatory T cell; TCR, T-cell receptor; Treg, regulatory T cell.
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inhibitory effects on Teffs, one of the main functions of activated
nTregs is to promote the generation of peripherally induced Tregs
(iTregs) in an antigen-specific and -non-specific manner (Figure 2).
Thus, the antigenic profile of nTregs partially overlaps with that of
iTregs. In the case of antigen-non-specific Treg induction, the slight
but frequent antigen priming tends to induce iTregs. Because Treg
activation, proliferation and induction require challenge of specific
antigens, and most of the antigens received by the lymph nodes are
those coming from the draining tissues under physiological conditions, Tregs in the lymph node mainly recognize antigens frequently
released from the draining tissues. Therefore, the antigenic profile of
Tregs may vary among different lymph nodes.
Although iTregs are not efficiently induced in the absence of nTregs
during the early life of an individual, the iTreg itself, once it reaches a
steady state, can promote the development of a second generation of
iTregs, and the peripheral Treg pool no longer requires nTreg supplementation (Figure 2). iTregs may be even more frequent than nTregs
after the start of thymus degeneration.
ANTIGEN-NON-SPECIFIC REGULATION OF PERIPHERAL
BALANCE BETWEEN TREGS AND TEFFS
The primary aim of the immune system is to clear invading pathogens;
however, excessive responses result in self-damage. Activation-induced
cell death might be an intracellular mechanism to control excessive
immune responses, but this negative feedback may be unable to detect
an excessive response that threatens to cause self-destruction. Here,
we propose that antigen-non-specific interplay between Tregs and
Teffs is one of the three most important mechanisms for preventing
self-inflicted damage. First, activated Tregs inhibit the activation, proliferation and activity of Teffs, but activated Teffs synergize with Tregspecific antigens to promote the activation, proliferation and activity of
Tregs. Second, without the help of activated Teffs, Tregs remain at low
levels of activation and proliferation and are susceptible to apoptosis.
Third, the interplay is antigen-non-specific in most cases, whereas the
activation of both Tregs and Teffs is antigen-specific. Although the
suppression mediated by antigen-specific Tregs is more effective than
that of polyclonal Tregs, it is unlikely that antigen-specific Tregs are
often involved in negative feedback. If tolerance has been maintained
by antigen-specific Tregs, subsequent antigen challenge may not lead to
excessive responses. If excessive responses have been triggered by the
dominance of Teff over Treg levels, there may be little chance to
generate enough Treg numbers in an antigen-specific manner because
activated Teffs inhibit the induction of Tregs from Tnais.5
In light of the abovementioned Treg antigenic profile, the nonspecific interplay between Tregs and Teffs may occur most often
between the draining tissue-derived self-antigens and invading foreign
antigens. The antigen non-specific model might advance our understanding of how the immune system regulates the balance between
mounting a response to pathogens and avoiding self-destruction.
Under physiologic conditions, T cells in the peripheral lymphoid
organs are frequently, but slightly, challenged by self-antigens, especially the draining organ-specific antigens. These self-antigens are
preferentially presented to Tregs by APCs. As a result, the potentially
pathogenic response to self-tissues is controlled. On the other hand,
when Tregs are challenged by specific antigens in the absence of help
from activated Teffs, Tregs frequency cannot increase much. Once
newly encountered antigens are of a sufficient dose, Teffs would be
readily induced and activated, resulting in amplification of an immune
defense cascade. When a strong immune response brings about selfdestruction, organ-specific self-antigens from damaged tissues are
released in proportion to the extent of destruction, and these antigens
are presented to Tregs in the draining lymph nodes. The proliferation
and activity of self-reactive Tregs are increased via the synergy between self- and foreign antigens, establishing a negative feedback
mechanism to counteract excessive response in an antigen-non-specific
manner. After clearance of pathogens, self-reactive Tregs decrease to
homeostatic levels. If an infection becomes chronic, the elevated activity and numbers of self-reactive Tregs help the low dose of foreign
antigens to induce additional specific Tregs. Self-reactive Tregs may
also suppress B-cell responses to foreign antigens in an antigen-nonspecific manner.
EVIDENCE IN SUPPORT OF THE HYPOTHESIS
The novel antigen-non-specific model is based on the findings of a
number of recent studies. In vitro studies have shown that Tregs
require TCR engagement for their activation. However, once activated,
Tregs can suppress both CD41 and CD81 T cells in a non-specific
manner.18 An in vivo model has also shown that antigen-specific
Tregs displayed broad suppression of the induction of experimental
autoimmune encephalomyelitis.19 Tregs preferentially recognize selfantigens.20,21 There are always baseline levels of activated Tregs in the
steady state.21–23 Continuous low-dose antigen stimulation has led to
Treg-mediated tolerance.24 In vitro studies have shown that Tregs can
be induced from CD41CD252Foxp32 Tnais and that Treg itself
facilitates this induction.4,10,11 Foreign antigen-specific Tregs can be
induced in vivo under certain circumstances during antigen exposure.25,26 IL-2 is produced mainly by activated Teffs but not Tregs
and can promote Treg proliferation.27 Tregs play a central role in
infectious tolerance.28 The self-injury caused by burns can enhance
the suppressive activity of Tregs and inhibit both the innate and
adaptive immune responses.29
The interplay between self- and foreign antigens has also been
observed recently. We found that simultaneous administration of
bowel tissue antigens attenuated the immune responses to enteric
bacterial antigens and raised the frequency of Tregs in mesenteric
lymph nodes (Hu GZ, Zheng SG, unpubl. data, 2010).
CONCLUSIONS
In developing this hypothesis, we highlighted Treg-centered antigennon-specific regulation with a focus on the interactions between selfreactive Tregs, which recognize antigens from the draining tissues, and
Tnais challenged by new antigens. The interactions may be commonly
involved in tolerance or immune establishment of adaptive immunity
to new antigens and in feedback control of excessive responses to
pathogens.
This hypothesis may provide new insights into therapeutic strategies for immunity-related diseases. Concurrent administration of
certain types of self-antigens and objective antigens may favor the
induction of antigen-specific tolerance. This may be particularly feasible for the induction of transplantation tolerance.
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