Resolving the identity myth: Key markers of functional CD4+FoxP3+ regulatory T cells

doi:10.1016/j.intimp.2011.05.018

International Immunopharmacology

Volume 11, Issue 10, October 2011, Pages 1489-1496

https://doi.org/10.1016/j.intimp.2011.05.018 Get rights and content

Abstract

Authenticating markers for the functional suppressive CD4⁺FoxP3⁺ regulatory T cells (Tregs) are important for the quantitative identification and enrichment of viable Tregs for possible therapeutic use. CD25 as a surrogate marker of Tregs has some limitations, which prompted investigators to identify more specific marker(s) of Tregs. The search for a firm molecular definition of Tregs resulted in the identification of FoxP3 as a better marker of this subset of CD4 cells. Nevertheless, FoxP3⁺ Tregs are phenotypically and functionally heterogeneous. Even in normal mice, only a minority of FoxP3⁺ T cells are potent suppressor cells. Therefore, additional marker(s) are required for delineation of truly functional Tregs. In this review, the studies identifying markers of functional Tregs, both in mouse and in human, and their functional implications are discussed. Our finding that TNFR2, which mediates the effect of TNF on the activation of Tregs, is a superb marker of the most suppressive subset of mouse Tregs and its application in the identification of functional human Tregs will also be reviewed.

Highlights

► FoxP3⁺ Tregs are phenotypically and functionally heterogeneous. ► Additional markers are needed to identify highly potent functional Tregs. ► A number of molecules or their combinations have provided useful tools in the delineation of functional Tregs. ► Identification of these molecules also has advanced our understanding of biological processes of Tregs. ► Identification of a more specific Treg cell marker(s), especially if expressed on the surface of functional Tregs, is still needed.

Introduction

There is compelling evidence that CD4⁺FoxP3⁺ regulatory T cells (Tregs) play an indispensable role in the maintenance of immune homeostasis and prevention of autoimmunity, however, they also dampen host immune responses against pathogens and represent a major cellular mechanism by which tumors evade immunosurveillance [1], [2]. As central regulator of immune responses, Tregs are considered to be important therapeutic target. Pharmacological manipulation of number and/or immunosuppressive function of Tregs has potential to be useful in the treatment of a number of major diseases, such as autoimmune disorders, allograft rejection, graft-versus-host disease and cancer [1], [2].

Reliable surface markers are a prerequisite for the quantitative identification and enrichment of viable Tregs. Utilization of CD25 to define Treg, especially in human, is problematic, because this receptor is also expressed by activated effector T cells (Teffs). In addition, Tregs in both humans and mice are phenotypically and functionally heterogeneous. This prompted the investigators to search for more specific Treg markers, as well as markers which can identify functional subset of Tregs. It is clear now that Tregs express a panel of co-stimulatory/co-inhibitory molecules (CD28, CTLA-4, ICOS and PD-1 etc.), TNF receptor super family (TNFRSF) members (TNFR2, GITR, OX40, 4-1BB and FAS, etc.), chemokine receptors (CCR2, -4, -5, -6, -7 and -8, CXCR3 and -4, etc.) and TLRs (such as TLR1, -2, -4, -5, -6, -7, -8 and -9), as previously reviewed [3], [4], [5], [6]. We will therefore focus on a number of molecules crucial for the delineation of functionality of Tregs. In an effort to unveil the mechanism underlying the activation of Tregs in the inflammatory environment, our laboratory unexpectedly found that TNF preferentially activates Tregs through TNFR2 [7]. Furthermore, the expression of TNFR2 actually identifies the maximally suppressive subset of mouse and human Tregs [8], [9], including CD4⁺ as well as CD8⁺ Tregs [10], [11].

Besides FoxP3⁺ Tregs, there are other types of Tregs that can be induced from naïve CD4 cells in the periphery during immune responses, such as IL-10-producing Tr1 cells [12] and TGFβ-producing Th3 cells [13]. In this review, our discussion will focus on the subset of naturally occurring, thymic-derived FoxP3⁺ Tregs.

Section snippets

CD25

Sakaguchi initially reported that transfer of purified CD4⁺CD25⁺ cells inhibited naïve CD4 cell-mediated autoimmunity in lymphopenic mice, and the lack of CD4⁺CD25⁺ cells was also responsible for the autoimmunity developed in neonatally thymectomized mice [14]. Although CD45RB^low was also identified as a marker of CD4 Tregs [15], only the CD25-expressing CD45RB^low cells were suppressive [16]. The in vitro model system that mimics the function of Tregs in vivo, established by Thornton/Shevach

FoxP3

The search for a firm molecular definition of Treg lineage resulted in the identification of Foxp3 [27], [34], [35]. Foxp3 is generally considered as a master regulator of biological processes of Tregs, including lineage commitment and developmental differentiation. This conclusion is favored by the study in Scurfy mice, a strain with X-linked autoimmune disease and dysregulated T cell function caused by disabling mutation of FoxP3 [36]. However, instead of being a monomorphic lineage

CTLA-4

CTLA-4 (CD152) down-regulates T cell activation by competing with CD28 for B7 binding. CTLA-4 is constitutively expressed by approximately ~ 40% of mouse Tregs [16], [43], and also rapidly induced in Teffs upon activation [43]. This molecule is reported to be critically required for the function of Tregs in vivo [44]. However, Tregs from CTLA-4-deficient mice are still functional [45]. The expression levels of CTLA-4 should be able to indicate functional status of Tregs. Indeed, mouse Tregs with

HLA-DR

HLA-DR is expressed by approximately one third of effector Tregs in adult human PB. HLA-DR⁺ Tregs express higher levels of FoxP3 and are responsible for contact-dependent in vitro suppression, while the suppression by HLA-DR⁻ Tregs is initially mediated by IL-4 and IL-10 and later by a contact-dependent mechanism [47]. Activation and expansion of HLA-DR⁻ Treg cells in vitro lead to the generation of HLA-DR⁺ Treg cells [47], [48]. Both ex vivo-isolated and in vitro-generated HLA-DR⁺ Treg cells

CD103

10–30% of mouse peripheral Tregs express CD103 [50], [51], [52]. In contrast to CD25, the expression of CD103 is not induced upon activation, and therefore is not an indicator of activation status of Tregs [51]. However, the in vivo inflammatory environment appears to up-regulate CD103 expression on Tregs [50], [53]. Although exhibiting an activated phenotype [52], [54], in vitro suppressive capacity of CD103⁺ Tregs is marginally higher than that of CD103⁻ Tregs [52], [54]. CD103⁺ Tregs express

CCR6

In the periphery, CCR6 is preferentially expressed by 15–32% of mouse Tregs. CCR6⁺ Tregs are generated in vivo from CCR6⁻ Tregs after encounter with antigen, and CCR6⁺ Tregs exhibit an effector–memory phenotype, although they possess equal suppressive ability as CCR6⁻ Tregs [63]. They respond rapidly to re-stimulation in vitro with up-regulation of IL-10. CCL20, the chemokine ligand for CCR6, can induce robust chemotactic response by CCR6⁺ Tregs [63]. In the mouse experimental autoimmune

CD127

Mouse Treg are generally characterized by low CD127 (IL-7R alpha) expression when compared with Teffs [69]. However, the expression levels of CD127 on mouse Tregs vary, depending on their localization and activation status. ICOS- and CD103-expressing Tregs express higher levels of CD127. Mouse Tregs significantly up-regulate their CD127 expression during in vitro and in vivo activation, and Tregs in bone marrow and skin also express high levels of CD127 [70].

Absence of CD127 together with CD25

CD45RO/CD45RA

CD45RO and CD45RA are exclusively expressed by distinct subsets of human CD4 cells, and can be used to divide human CD4⁺FoxP3⁺ T cells into three phenotypically and functionally distinct subpopulations: CD45RA⁺CD25⁺FoxP3^low resting Treg cells and CD45RO⁺CD25^highFoxP3^high activated Treg cells, both of which were suppressive in vitro, and proinflammatory cytokine-producing CD45RO⁺CD25⁺FoxP3^low nonsuppressive Teffs [31]. Human CD4⁺ FoxP3⁺ T cells with a naive phenotype (expressing CD45RA)

ICOS

Co-stimulatory receptor ICOS is expressed by the majority of mouse Tregs, and FoxP3^highCD44^high Tregs express higher level of ICOS [79]. In a model of contact hypersensitivity, a subset of FoxP3⁺ Tregs expressing high levels of ICOS possesses superior suppressive activity. Distinct from other subset FoxP3⁺ Tregs, ICOS⁺ Tregs in this model also produce IL-10, IL-17 and IFNγ [80]. In other models, Tregs highly expressing ICOS have the capacity to express IL-10 [81], [82], therefore can be

LAG-3

LAG-3 (lymphocyte-activation gene 3), a ligand of MHC II, can be induced on activated T cells and negatively regulates T cell homeostasis by Treg-dependent and independent mechanisms [84]. Mouse Tregs selectively express high levels of the LAG-3 gene, however, surface expression of LAG-3 protein on Tregs can only be detected on ex vivo TCR-activated Tregs, not on freshly isolated Tregs [85]. Interestingly, LAG-3 is constitutively expressed on IL-10-producing CD4⁺CD25⁻FoxP3⁻ cells [86] and may

GARP

The gene encoding GARP (glycoprotein A repetitions predominant, also known as leucine-rich-repeat-containing protein 32 or LRRC32), a cell surface molecule, is expressed 100 fold more by activated human Tregs as compared with Teffs [89], [90]. Upon activation, GARP is expressed on a subset of CD25⁺ (or FoxP3⁺) Tregs which has more potent suppressive capacity as compared with GARP⁻CD25⁺ cells which contain IL-17-producing cells. Expression of GARP is associated with FoxP3 expression and

LAP/CD121a/CD121b

Latency-associated peptide (LAP) and IL-1 receptor type I (CD121a) and II (CD121b) are not expressed constitutively on resting or expanded FoxP3⁺ Tregs, but are rapidly induced and expressed only on FoxP3⁺ Tregs for a short period after TCR-mediated activation. These three molecules are selectively expressed on activated Tregs with fully suppressive capacity, but not expressed on either activated CD4⁺FoxP3⁻ Teffs, or by proinflammatory cytokine-producing FoxP3⁺ non-suppressive cells and

CD39

In PBMCs from normal humans, CD39 is expressed almost exclusively by ~ 60% of Foxp3⁺ cells. There is a linear correlation of expression of CD39 and FoxP3 [97]. The mechanism of suppression by CD39 (nucleoside triphosphate diphosphohydrolase-1 [NTPDase 1]) is based on inactivation of extracellular proinflammatory ATP. CD39⁺ Tregs co-express CD45RO and CCR6, thus they represent a subset of activated effector/memory-like Tregs [97]. Although both CD4⁺CD25^highCD39⁺ and CD4⁺CD25^highCD39⁻ T cells

CD49d

CD49d, alpha chain of the integrin VLA-4 (α4β1), is expressed on the majority of proinflammatory PBMCs but is absent on Tregs [100]. Therefore, exclusion of CD49d⁺ cells can be used to remove the contaminating IFNγ- and IL-17-producing CD25⁺ Teffs from CD25⁺ Tregs. The purity of Tregs can be further enriched by removal of CD49d⁺/CD127⁺ cells. The resultant CD4⁺CD25^highCD49d⁻CD127⁻ cells yield Foxp3⁺ Tregs virtually free of contaminating CD25⁺ Teffs [100]. Thus, the absence of CD49d may be used

TNFR2

Our studies show that the classical proinflammatory cytokine TNF exerts a negative feedback activity on inflammatory responses by activating and expanding Tregs through TNFR2 [7], [101]. TNFR2 is preferentially expressed by 30–40% of Tregs present in the peripheral lymphoid tissues of normal mice, while fewer than 10% of Teffs express TNFR2 at lower levels on a per cell basis [8], [24]. TNFR2-expresssing CD25⁺ cells or FoxP3⁺ cells exhibited the most potent suppressive activity, while TNFR2⁻

Closing remarks

A number of molecules or their combinations have been shown to be able to identify functional suppressive Tregs in mouse or humans, as summarized in Table 1, Table 2. These molecules, although diverse in nature, collectively have provided useful tools in the delineation of functional Tregs, and advance our understanding of biological processes and suppressive mechanisms of this important subset of CD4 cells. Most of these “Treg markers” are also expressed by activated Teffs, nevertheless, in

Acknowledgment

The authors thank Drs. Ji Ming Wang and Wan Jun Chen for discussion and critical review of the manuscript. The authors apologize to those researchers whose work could not be cited due to space limitations.

This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. This Research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for

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ReviewResolving the identity myth: Key markers of functional CD4+FoxP3+ regulatory T cells☆

Abstract

Highlights

Introduction

Section snippets

CD25

FoxP3

CTLA-4

HLA-DR

CD103

CCR6

CD127

CD45RO/CD45RA

ICOS

LAG-3

GARP

LAP/CD121a/CD121b

CD39

CD49d

TNFR2

Closing remarks

Acknowledgment

Immunity

Microbes Infect

Blood

Trends Immunol

Microbes Infect

Am J Pathol

Blood

Immunity

Mol Ther

Blood

Blood

Immunity

Blood

J Allergy Clin Immunol

Blood

Blood

Immunity

Cell Immunol

Blood

Blood

Blood

Immunity

Immunity

Blood

Blood

Immunity

Blood

Am J Transplant

Blood

Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self

Nat Immunol

Function of tumor necrosis factor receptor family members on regulatory T-cells

Immunol Res

Interaction of TNF with TNF receptor type 2 promotes expansion and function of mouse CD4+CD25+ T regulatory cells

J Immunol

Cutting edge: expression of TNFR2 defines a maximally suppressive subset of mouse CD4+CD25+FoxP3+ T regulatory cells: applicability to tumor-infiltrating T regulatory cells

J Immunol

Co-expression of TNFR2 and CD25 identifies more of the functional CD4+FOXP3+ regulatory T cells in human peripheral blood

Eur J Immunol

Acquisition of regulatory function by human CD8(+) T cells treated with anti-CD3 antibody requires TNF

Eur J Immunol

Critical role for TNF in the induction of human antigen-specific regulatory T cells by tolerogenic dendritic cells

J Immunol

Interleukin-10-secreting type 1 regulatory T cells in rodents and humans

Immunol Rev

Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells

Immunol Rev

Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases

J Immunol

OX-22high CD4+ T cells induce wasting disease with multiple organ pathology: prevention by the OX-22low subset

J Exp Med

Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation

J Exp Med

CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production

J Exp Med

Homeostasis of peripheral CD4+ T cells: IL-2R alpha and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers

J Immunol

Competition for cytokines: T(reg) cells take all

Review
Resolving the identity myth: Key markers of functional CD4⁺FoxP3⁺ regulatory T cells☆

Naturally arising Foxp3-expressing CD25⁺CD4⁺ regulatory T cells in immunological tolerance to self and non-self

Interaction of TNF with TNF receptor type 2 promotes expansion and function of mouse CD4⁺CD25⁺ T regulatory cells

Cutting edge: expression of TNFR2 defines a maximally suppressive subset of mouse CD4⁺CD25⁺FoxP3⁺ T regulatory cells: applicability to tumor-infiltrating T regulatory cells

Co-expression of TNFR2 and CD25 identifies more of the functional CD4⁺FOXP3⁺ regulatory T cells in human peripheral blood

OX-22high CD4⁺ T cells induce wasting disease with multiple organ pathology: prevention by the OX-22low subset

CD4⁺CD25⁺ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production

Homeostasis of peripheral CD4⁺ T cells: IL-2R alpha and IL-2 shape a population of regulatory cells that controls CD4⁺ T cell numbers

Repertoire requirements of CD4⁺ T cells that prevent spontaneous autoimmune encephalomyelitis

CD25⁺ CD4⁺ T cells regulate the expansion of peripheral CD4 T cells through the production of IL-10

Expression of costimulatory TNFR2 induces resistance of CD4⁺FoxP3- conventional T cells to suppression by CD4⁺FoxP3⁺ regulatory T cells

CD4⁺CD25⁺Foxp3⁺ T cells and CD4⁺CD25-Foxp3⁺ T cells in aged mice

An essential role for Scurfin in CD4⁺CD25⁺ T regulatory cells