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International Immunology Advance Access originally published online on May 23, 2006
International Immunology 2006 18(7):991-1000; doi:10.1093/intimm/dxl044
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review-article

Emerging possibilities in the development and function of regulatory T cells

Kajsa Wing1, Zoltán Fehérvári1 and Shimon Sakaguchi1,2

1 Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Shogoin 53, Kawahara-cho, Sakyoku, Kyoto 606-8507, Japan
2 Core Research for Evolutional Science and Technology (CREST) Program, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan

Correspondence to: K. Wing; E-mail: kajsa{at}frontier.kyoto-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Treg taxonomy
 Thymic development of nTreg
 Peripheral development of murine...
 Suppressive mechanisms
 Concluding remarks
 References
 
CD25+CD4+ Regulatory T cells (Treg) represent a unique population of lymphocytes capable of powerfully suppressing immune responses. A large body of experimental data have now confirmed the essential role played by these cells in a host of clinically relevant areas such as self-tolerance, transplantation, allergy and tumor/microbial immunity. Despite this mass of knowledge, significant gaps in our understanding of fundamental Treg biology remain, particularly regarding their development and mechanisms of suppression. In this review we attempt to highlight the current controversies and directions in which this exciting field is moving.

Keywords: adaptive regulatory T cell, CTLA-4, Foxp3, natural regulatory T cells, tolerance


   Introduction
Top
 Abstract
 Introduction
Treg taxonomy
 Thymic development of nTreg
 Peripheral development of murine...
 Suppressive mechanisms
 Concluding remarks
 References
 
Distinguishing between self and non-self is a fundamental property of the immune system and a number of immunological ‘fail-safes’ exist to ensure that this is maintained effectively. First and foremost among these mechanisms is the purging of self-reactive T cells within the thymus by negative selection. Although highly efficient and of critical importance, negative selection is nevertheless fallible and there is ample evidence showing the presence of autoreactive and potentially pathologic T cells within the peripheral immune system (1). A secondary set of peripheral tolerizing mechanisms is thus required to avoid harmful autoimmunity and among these the influence of regulatory T cells (Treg) seems to have attained pre-eminence. Recent years have witnessed a startling interest in Treg, and their crucial role in maintaining self-tolerance has become almost axiomatic. The cardinal feature of Treg is their dramatic ability to suppress both adaptive and innate immune responses (2–4). This characteristic makes them important not just in maintaining immunological self-tolerance but more generally in the control of anti-microbial, anti-tumor and anti-graft responses. As such, Treg underlie a number of important clinical areas and effectively harnessing their natural suppressive ability would hold great therapeutic potential. Progress in the Treg field has been rapid and we now understand an impressive amount about how these cells function yet some confusion remains. Nowhere is this more pronounced than in Treg development and their mechanism of suppression. This review will try and clarify our current state of knowledge and highlight the controversies to which this field is heir.


   Treg taxonomy
Top
 Abstract
 Introduction
 Treg taxonomy
Thymic development of nTreg
 Peripheral development of murine...
 Suppressive mechanisms
 Concluding remarks
 References
 
Suppressive CD4+ T cells can be divided into two broad types of Treg, the so-called ‘naturally occurring’ regulatory T cells and ‘adaptive’ regulatory T cells, hereafter defined, respectively, as nTreg and aTreg (5). Although recently emerging data have rendered this distinction somewhat arbitrary (see later) it still serves as a useful classification, especially when considering the mouse system. What primarily distinguishes aTreg and nTreg are different developmental pathways and their mechanisms of suppression; this in turn seems to govern their respective immunological role. This distinction has led to the suggestion that nTreg are concerned primarily with maintaining self-tolerance and aTreg with ablating an ongoing immune response.

nTreg
These Treg are generated within the thymus and exit to the periphery with a stable and fully functional suppressive phenotype where they constitute ~5–10% of peripheral CD4+ T cells. nTreg constitutively express CD25 in normal naive mice and healthy humans and indeed, to date, this has proved to be by far the most useful surface marker for nTreg (6, 7). Moreover, CD25 is not a mere marker but is also functionally essential since it is a key component of the high-affinity IL-2R and nTreg are highly dependent on exogenous IL-2 for their maintenance (8). A number of other cell-surface molecules have been used to identify nTreg, among them CTLA-4 (CD152), {alpha}Eß7-integrin (CD103), GITR (glucorticoid-induced tumor necrosis factor family-related gene/protein) and neuropilin-1 (9–14). However to date, no cell-surface molecule has been uniquely associated with Treg, but in most cases they are up-regulated by conventional T cells upon activation. To complicate matters even further, CD25 non-expressing Treg also exist in small numbers as fully functional suppressive cells (15, 16).

A large body of experimental data demonstrate the crucial role played by nTreg in maintaining self-tolerance. For instance, adoptive transfer of CD4+ T cells depleted ex vivo of CD25+ cells to athymic mice elicits a variety of autoimmune diseases such as thyroiditis, gastritis and insulitis. On the other hand, co-transfer with CD25+CD4+ cells inhibits such disease development (7, 17). Indeed, the frequency and severity of autoimmune disease induction seems to correlate closely with the extent of nTreg depletion (16). Other studies have demonstrated the ability of nTreg to suppress a variety of immune responses in vivo including those to allografts, tumors and microbes (18–22). In vitro nTreg are observed to be potently suppressive in a contact-dependent manner (see later), but curiously they are themselves profoundly anergic (17, 23). Since nTreg proliferate readily in vivo under both steady-state and lymphopenic conditions, this anergy probably just reflects an in vitro insufficiency of appropriate stimulatory ligands (8, 24). Indeed, nTreg seem to behave similar to other T cells in vivo, as they can persist without antigen stimulation for long periods of time, re-circulating between blood and lymph and then home to antigen-draining lymph nodes where they effectively expand (25–27). These are important requirements when considering the suppressive mechanism of nTreg in vivo.

aTreg: T regulatory type 1 and Th3 cells
A variety of experimental approaches can lead to the generation of suppressive aTreg, with somewhat variable properties and as such they probably represent a heterogeneous group of cells. Depending on the method and mode of generation, aTreg can be classed as either T regulatory type 1 (Tr1) or Th3 cells (28, 29). Tr1 cells can be generated by activation in the presence of the immunomodulating cytokine IL-10 (30). Tr1 cells secrete a pattern of cytokines distinct from that of Th1 and Th2 effector cells and are characterized by high levels of IL-10 and generally low levels of transforming growth factor (TGF) ß and IL-5. In addition, Tr1 cells are anergic, functionally suppressive in vitro and are able to prevent the development of experimentally induced Th1 autoimmune diseases such as colitis when transferred in vivo (30). A number of other ex vivo experimental treatments have also led to the generation of Tr1-like cells, for instance stimulation of conventional CD4+ T cells by immature or cytokine-modified dendritic cells (DCs) (31–33). A common principle which may underlie such tolerizing DCs is their unique pattern of stimulatory ligands, e.g. high MHC class II coupled to low co-stimulation (CD80 and CD86). Another study identified a DC subset responsible for the generation of regulatory cells in vivo (34). Such DCs possessed plasmacytoid morphology and expressed the CD45RB molecule. Previously, the in vivo significance of Tr1-like cells was unclear; therefore, finding a pathway to their generation by the action of a physiologically occurring DCs has important implications. Other molecular signals which seem to play a role in Tr1 generation in either human or murine systems (not necessarily in the presence of DCs) appear to be those acting through CD2, Notch-1 and the complement receptor CD46 (35–39). Finally, it is also possible to generate regulatory cells ex vivo by treating human and mouse T cells with the pharmacological immunosuppressants vitamin D3 and dexamethasone (40, 41). These cells appear to be distinct from the previously characterized Tr1 cells in that they appear to solely secrete IL-10 as well as retain a robust in vitro proliferative capacity.

Th3 cells were first cloned out from the mesenteric lymph nodes of mice orally tolerized with myelin basic protein (28). Such cells preferentially secrete TGF-ß together with varying amounts of IL-4 and IL-10 and are able to suppress the induction of experimental autoimmune encephalitis by TGF-ß-dependent mechanisms. In vitro differentiation is enhanced by the addition of TGF-ß, IL-4 and IL-10 and anti-IL-12 antibody, while induction in vivo is improved by oral administration of IL-4 (42). The intestinal mucosa has high basal levels of TGF-ß, IL-4 and IL-10, which are up-regulated after the administration of antigen (43). It is therefore conceivable that this environment is important for the generation of these cells. Th3-like cells have also been shown to be important in the control of a variety of other experimental autoimmune disease models. Some clinical data have also observed a perturbation of TGF-ß/Th3 function in some cases of human autoimmunity and allergy (44, 45).


   Thymic development of nTreg
Top
 Abstract
 Introduction
 Treg taxonomy
 Thymic development of nTreg
Peripheral development of murine...
 Suppressive mechanisms
 Concluding remarks
 References
 
Several studies show that nTreg are generated within the thymic medulla most likely in response to high-affinity interactions with thymic epithelial cells (TECs) (46–48). However, if the selection events of nTreg are solely reserved for TECs in the medulla is not clear since experiments with K14 mice which exclusively express MHC class II on the cortical epithelium demonstrate that this too is sufficient for the development of nTreg (49). Furthermore, recent data suggest the epithelial cells of Hassal's corpuscles to be indirectly involved in development of nTreg by producing thymic stromal lymphopoietin (TSLP) which activates thymic CD11c+ DCs in the thymic medulla to express high levels of CD80/86 (50). These TSLP-activated DCs can induce an nTreg phenotype in human CD4+CD8–CD25– thymocytes in vitro and this is dependent on interactions with MHC class II and CD80/86 (50). Thus, even though Hassal's corpuscles are poorly developed in rodents, this may be important for nTreg differentiation in humans. Besides TCR–ligand interactions, there may be other specialized pathways responsible for nTreg development, most notably the CD28–B7 axis (51, 52). Additionally, molecular interactions that alter the overall avidity of a developing T cell for a TEC, such as the adhesion molecule leukocyte function-associated antigen-1 (LFA-1), are almost certainly also important for nTreg development but the details of these ancillary signals remain largely ill-defined (53, 54). Within the thymus, developing nTreg undergo a slower ontogeny relative to CD4+ non-Treg, allowing an earlier egress of the latter, which facilitates the experimental induction of autoimmunity by neonatal thymectomy (46). The differences in thymic development of nTreg and conventional T cells are further seen in evidence from TCR transgenic mice which demonstrates that a large proportion of nTreg express TCRs composed of endogenous {alpha}- and transgenic ß-chains as opposed to the bulk of conventional CD4+ cells which utilize entirely transgene-derived TCRs (55, 56). Disruption of endogenous TCR-{alpha} gene rearrangement by using recombination activating gene RAG2-deficient mice abrogates the development of CD25+CD4+ Treg (55, 56). However, in animals with a high-affinity transgenic TCR and antigen continuously present during thymic development, the opposite occurs and it is nTreg that are equipped with the transgenic TCR while conventional T cells have endogenous {alpha}- and transgenic ß-chains (47, 57). Together, this suggests that the affinity of the TCR is indeed important for the development of nTreg.

The identification of the transcriptional repressor Foxp3 (FOXP3 in humans) as being critical for nTreg development and function represented a huge leap forward in our understanding of Treg biology (58–60). Experiments in mice have demonstrated Foxp3 to be specifically expressed in nTreg (CD25+ and CD25–), appearing first at the thymic CD4CD8 double-positive stage (46, 58–61). In contrast to all the cell-surface markers used to date, Foxp3 was never observed in non-Treg following conventional activation or differentiation into Th1/Th2 cells, nor could it be detected in NKT cells. Furthermore, aTreg of various forms do not appear to express Foxp3 (41). Critically, transduction of Foxp3 into Foxp3– non-regulatory T cells bestows them with a fully functional nTreg phenotype; e.g. they up-regulate classic nTreg markers and their adoptive co-transfer with CD25–CD4+ T will prevent autoimmune disease in SCID mice (58, 60). Loss of function mutations of Foxp3 (the scurfy mouse) or its targeted deletion, engenders an inability to develop nTreg, resulting in a highly dysregulated immune system. Such mice show large numbers of chronically activated T cells and rapidly succumb to rampant inflammatory disease (60, 62). Thus, Foxp3 appears to be a master control gene for the development and function of nTreg.

Broadly speaking, an equivalent pattern of FOXP3 expression is also reported in human cells, with Treg cell-like properties being similarly transferable by retroviral transduction (63–66). IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) is the human counterpart to the scurfy mouse and is again caused by mutations in FOXP3 resulting in a very similar disease phenotype (67). However, some discrepancies do exist in the behavior of human and mouse FOXP3/Foxp3 expression. There have been some reports that FOXP3 is induced following CD3/CD28 antibody-mediated activation of normal CD25– human T cells, which is not normally observed in the murine model (64). Similarly, some instances of CD25– human T cell activation by DCs has also resulted in FOXP3 up-regulation (31, 68). This said, another report failed to observe up-regulation of FOXP3 after CD3/CD28 antibody stimulation of CD25– T cells (65). Thus, there is some controversy as to the significance of FOXP3 up-regulation in otherwise normal T cells, and it remains possible that its detection simply represents an enrichment of contaminating nTreg rather than their de novo generation.


   Peripheral development of murine naturally occurring Foxp3+ Treg
Top
 Abstract
 Introduction
 Treg taxonomy
 Thymic development of nTreg
 Peripheral development of murine...
Suppressive mechanisms
 Concluding remarks
 References
 
As discussed above, it was initially unclear as to whether Foxp3+ Treg could develop at all outside of the thymus in the mouse system. In contrast to human Treg, it appeared that murine Treg developed solely within the thymus as a terminally differentiated and functionally mature population. However, some very recent reports have demonstrated a hitherto unappreciated plasticity in mouse Treg development which may have important implications for their role in immunohomeostasis.

Development by antigenic stimulation
One of the first pieces of evidence for the peripheral development of Foxp3+ Treg emerged from a reappraisal of the so-called ‘low zone’ tolerance (69). This phenomenon was first observed decades ago and describes the antigen-specific tolerance resulting from stimulation by sub-immunogenic doses of antigen given intravenously (70). Using an osmotic pump system to deliver minute, controlled quantities of antigenic peptide to TCR transgenic mice, the authors could demonstrate the appearance of CD25+CD4+ Treg measurable by their function, phenotype and Foxp3 expression. Most convincingly, such Foxp3+ Treg development occurred using thymectomized TCR transgenic mice on a RAG knockout (KO) background, which possess a monoclonal TCR repertoire and are conventionally thought to lack Foxp3+ nTreg. A second demonstration of peripheral Treg development used a similar TCR transgenic system (again from a RAG KO background). Such cells were transferred into lymphopenic mice transgenically expressing their cognate antigen systemically as a serum protein (71). T cells transferred in this way were dramatically activated and induced a graft versus host disease (GvHD) which in most cases resolved spontaneously. Resolution of GvHD appeared to be entirely dependent on the de novo appearance of Foxp3+ Treg cells. IL-2 secreted from effector cells seemed to be essential for driving the peripheral generation of Treg, therefore providing a direct link between pathogenic cells and those cells which would regulate them. IL-2 seems to have an important relationship with nTreg, indeed IL-2 and IL-2R KO mice show a severe multiorgan autoimmunity typically attributed to a relative lack of nTreg (8, 24, 72, 73). However, the most recent analysis of IL-2 KO mice using a Foxp3–GFP knock-in demonstrated that nTreg did in fact develop in the absence of IL-2 signaling and autoimmunity was instead a consequence of ineffective nTreg peripheral homeostasis (74).

The role of TGF-ß
Another possible mode of peripheral nTreg generation is through the action of TGF-ß. As described above, TGF-ß has been implicated in the suppressive function of Treg but potentially also in their extra-thymic generation. For example, the addition of nanogram quantities of exogenous TGF-ß to ex vivo cultures of conventional Foxp3– T cells results in the generation of suppressive Foxp3+ nTreg (61, 75). This may suggest that TGF-ß either has a direct effect on the Foxp3 promoter or somehow modifies a T cell's activation threshold and nudges it down a nascent Treg developmental program (76). The latter is backed by a recent study where hemagglutinin antigen was targeted to DCs by DEC-205 which resulted in the induction of Foxp3+ nTreg from naive RAG KO TCR transgenic T cells (77). Other than being another example of peripheral induction of nTreg, the authors concluded that successful induction was improved by sub-immunogenic conditions and ability to respond to TGF-ß. In vitro stimulation with anti-CD3 and anti-CD28 alone also appears to induce a low frequency of Foxp3 but this is most likely triggered by endogenous TGF-ß (61). TGF-ß also appears to serve in the physiological optimization of nTreg function, in a manner similar to IL-2, in particular through the maintenance of Foxp3 expression (78–80). Finally, there is also evidence to suggest that non-depleting anti-CD4 mAbs may induce Foxp3+ nTreg both in vitro and in vivo via the action of TGF-ß, but in this instance the source and trigger of TGF-ß is unclear (81).

Collectively then it appears that fully functional Foxp3+ nTreg may be generated from conventional non-regulatory CD4+ T cells stimulated systemically by both endogenous and exogenous candidate antigens (Fig. 1). One obvious caveat to note is that these studies made exclusive use of similar TCR transgenic systems under varying conditions of lymphopenia and in so doing may represent a developmentally skewed population. Likewise, if one considers the role of TGF-ß, are the required concentrations of cytokine supplied in vitro ever really attained in vivo? Such issues aside, the possibility of peripheral nTreg development raises a number of interesting theoretical issues. For example, is it the case that a certain number of ‘de facto’ nTreg develop as a consequence of any immune response primed to systemic antigen, endogenous or otherwise? More relevantly, what is the physiological significance, if any, of this peripheral development? In the case of a pathogen response, one could readily speculate that both effector cells and nTreg could be generated to the same exogenous antigen, with the latter population primed, expanded and ready to bring an immune response under control once pathogen-associated molecular patterns (PAMPs) antagonistic to nTreg suppression had been cleared. Peripherally generated Foxp3+ nTreg would thus assume the role more normally ascribed to the so-called aTreg mentioned above and in so doing somewhat blur the distinction made between this population and its nTreg counterparts. Although clearly suppressive in a contact-dependent manner, it is unclear whether peripherally generated Foxp3+ nTreg are functionally equivalent to thymically produced nTreg or differ in a subtle way not borne out by standard in vitro Treg assays.


Figure 1
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  		Fig. 1 Development of various T cell subsets including Treg. Conventional CD4+ T cells and Treg originate in the thymus from a common precursor whereupon they exit to the periphery as naive Th0 and fully functional Foxp3+ Treg, respectively. Immunogenic stimulation of Th0 cells results in their differentiation to effector Th1 and Th2 cells which engage in productive immune responses. Stimulation of Th0 cells under a variety of specialized in vitro conditions or via an oral route can result in a Foxp3– adaptive regulatory cell. These suppressive cells mediate their action primarily by the anti-inflammatory cytokines IL-10 and TGF-ß. Furthermore, stimulation of Th0 in the presence of TGF-ß or systemic/low-dose antigen in vivo results in a Foxp3+ Treg that to all intents and purposes appears indistinguishable from their naturally occurring counterparts. The significance of this developmental plasticity remains to be determined. Ag, Antigen; VitD3, vitamin D3; Dex, dexamethasone.

 
The fact that Foxp3+ Treg could develop within a monoclonal T cell population, implicates some parameter other than TCR specificity/affinity as being responsible for their peripheral generation. Or to paraphrase, what is it about a particular naive CD4 T cell that allows it to up-regulate Foxp3+ and become an nTreg? Even in a TCR homogenous population, cell-surface parameters such as adhesion molecule expression could still exhibit considerable variation, enabling qualitative differences in T cell activation and potentially trigger an nTreg developmental trajectory. In this regard, specialized antigen-presenting cells (APCs) such as the so-called ‘tolerogenic DCs’ may also have a crucial role to play though as yet there is no evidence that these generate Foxp3+ Treg (33, 34, 75, 82). Finally, it may be valid to question the idea of TCR transgenic cells on a RAG KO background as being ‘totally naive’ and free of Foxp3+ nTreg. Although T cells from such mice show very low levels of Foxp3 expression by quantitative PCR, it is nevertheless higher than that of B cells or fibroblasts, suggesting that even here there may be a subtle degree of nTreg pre-commitment (58).


   Suppressive mechanisms
Top
 Abstract
 Introduction
 Treg taxonomy
 Thymic development of nTreg
 Peripheral development of murine...
 Suppressive mechanisms
Concluding remarks
 References
 
The mechanism of suppression is a central question that despite intense research over the years remains controversial and unresolved. This is particularly true with regard to the nTreg mechanisms of action in vivo, something that may be wise to keep in mind when embarking on studies with nTreg as means or target of therapy. The effects of nTreg in vitro have been most thoroughly studied on CD4+ and CD8+ T cells but nTreg have also been reported to act directly on B cells, NK, NKT cells and different APCs (2, 83–87). Freshly isolated nTreg are not suppressive and require TCR interaction with a specific antigen or polyclonal stimulus to exert suppression. However, once activated, in vitro studies show that they suppress CD4+ and CD8+ T cells independently of antigen specificity by inhibiting the transcription of IL-2 in target cells (17, 23). Notably, IL-2R KO mice can be rescued by adoptive transfer of nTreg which suggests that targets other than IL-2 production are also affected (24). Indeed, IL-2 does not appear to be an essential growth factor in vivo for T cells except for nTreg and consequently the primary target of suppression remains unknown (74, 88, 89).

Suppression and cytokines
The majority of murine and human in vitro studies concludes that nTreg mediate suppression by a yet unknown cell-contact-dependent mechanism, which is independent of IL-10 and TGF-ß since blocking antibodies do not affect the suppression and nTreg isolated from IL-10- or TGF-ß-deficient mice are functional in vitro (17, 23, 90, 91). Having said this, others have found that by blocking TGF-ß1 bound to the cell surface of nTreg with specific antibodies, suppression is abrogated in vitro (92, 93). Both IL-10 and TGF-ß are cytokines with diverse immunosuppressive effects on the immune system which makes it difficult to assess their respective role as suppressive mechanisms of nTreg in vivo. However, IL-10 produced by nTreg seems important for the suppression of colitis since wild-type but not IL-10-deficient nTreg were found to be protective after adoptive transfer. Notably, autoimmune gastritis was found to be controlled independently of IL-10 which suggests that nTreg may utilize different means of suppression depending on the location of inflammation (94, 95). Regarding TGF-ß, its role in nTreg peripheral homeostasis, Foxp3 expression and general fitness makes it difficult to pin down the reasons for reduced suppressive capacity to the lack of a suppressive mechanism (78). The cellular sources of IL-10 and TGF-ß are numerous and clearly these cytokines are important for maintaining tolerance. Still, precisely how significant the contribution from nTreg is on the whole remains unclear and yet another possibility is that nTreg facilitates the production of IL-10 and TGF-ß from other T cells by the so-called infectious tolerance (96, 97). Furthermore, as nTreg were shown to induce production of IL-10 and TGF-ß of other T cells in a contact-dependent manner, this could reconcile some of the discrepancies seen between the in vivo and in vitro studies.

T–T-mediated suppression
One of the most consistent findings regarding nTreg suppression in vitro is their dependency on cell contact with target cells as shown by experiments utilizing transwell systems (17, 23, 90). Reductionist experiments show that APCs are not required for suppression since regulation is also observed in APC-free cultures in vitro (98). This suggests that nTreg can operate by directly inhibiting other T cells, something that has been explored by several groups. One line of investigation addresses the function of CD80 and CD86 present on activated T cells (99). Recently, it was proposed that ligation of mainly CD80 on T cell targets with CTLA-4 present on nTreg results in suppression by outside-in signaling (100). The authors concluded that this pathway was essential for regulation since B7-deficient T cells failed to be suppressed by wild-type nTreg. However, work in our laboratory show that CD4+ T cells from B7 KO mice can indeed be suppressed under similar conditions as wild-type cells (Zoltan Fehervari, unpublished data). Furthermore, CTLA-4 KO nTreg are suppressive in vitro which together speaks against B7 outside-in signaling as being a major route of nTreg suppression (101).

Recently, the possibility was raised that nTreg have cytolytic capabilities. Human nTreg were found to express Granzyme A after activation with a combination of antibodies to CD3 and CD46 while murine nTreg expressed Granzyme B after anti-CD3 stimulation (102–104). In the human study, nTreg were reported to kill a wide selection of cell types including T cells and APCs in a perforin-dependent way (104). Conversely, a recent murine study only detected killing of B cells and not CD4+ T cells when using re-stimulated nTreg and this was only partially dependent on perforin (102). These discrepancies are either due to specific means of activation or differences in species or both and remain to be elucidated. Regardless, in the literature there is currently little evidence of nTreg routinely killing target T cells since in vivo studies support the notion of reversible suppression of T cells and in vitro studies demonstrate down-regulation of IL-2 transcription in suppressed T cells within the first 24 h of culture while an increase in apoptosis could not be detected (17, 23, 105, 106). Thus, the question of whether nTreg actively kill T cells is debatable, at least as an early event in suppression. Interestingly, in murine nTreg Granzyme B was observed to be slowly up-regulated and peaked late during culture. Moreover, cytotoxic function required re-stimulation of nTreg which then only affected APCs and not bystander B cells (102). This suggests that nTreg may behave differently in the later stages of an inflammatory response and that a higher degree of control and specificity is observed compared with early suppressive events which are reportedly antigen non-specific. Still, it remains to be determined if nTreg killing of either T cells or B cells are events that actually take place in vivo.

Suppression and the role of APCs
As previously mentioned, suppression can take place in the absence of APCs. This, however, does not exclude the possibility that nTreg can control immune responses by affecting the activation state of the APCs or that certain signals from APCs to nTreg are vital for suppression in vivo. This is suggested by the fact that nTreg in vitro can down-regulate CD80 and CD86 and reduce the stimulatory capacity of APCs and conversely that different subsets of APCs can modulate nTreg suppression (85, 87, 107, 108). Until recently, little was known about interactions between nTreg and DCs or for that matter effector T cells in vivo. Tang et al. (109) used two-photon laser-scanning microscopy to study the in vivo events of antigen priming in the pancreatic lymph node of non-obese diabetic mice. Interestingly, during ongoing suppression, no stable association between nTreg and effector T cells was detected but instead nTreg interacted with antigen-presenting DCs which resulted in the prevention of effector T cell priming. Increasing evidence points to the DCs as the driving force in shaping the immune response and thus it seems reasonable that a major route of action by nTreg is directed through this cell population. The nature of this nTreg–DC interaction is unknown. Nevertheless, in current literature there are implications for a role of CTLA-4 (Fig. 2). For example, CTLA-4 expressed by nTreg can interact with CD80/86 on the DC inducing indoleamine 2,3-dioxygenase that leads to reduced levels of tryptophan in the localized environment and decreased activation of T cells (110). Another or possibly concurrent role of CTLA-4 in nTreg–DC interaction is its recently shown ability to modulate T cell adhesion by up-regulation of LFA-1 binding to ICAM-1 (111). Consequently, CTLA-4+ T cells adhere better than CTLA-4– cells and nTreg that express CTLA-4 constitutively may as a result alter the physical interactions between APCs and effector T cells. This idea is further supported by the fact that nTreg from LFA-1 KO mice are less potent suppressors both in vitro and in vivo (54). Collectively, this points to the importance of cell-contact-dependent suppression so repeatedly demonstrated in vitro. Several facts strongly suggest that CTLA-4 is important for nTreg functionality. Firstly, the only cells in naive animals or human cord blood that constitutively express CTLA-4 are CD4+CD25+ T cells (14, 112). Secondly, CTLA-4 KO mice share substantial similarities to scurfy mice which lack nTreg (59). Finally, addition of anti-CTLA-4 antibody or Fab fragments in vitro neutralizes nTreg suppression (14). The function of CTLA-4 is not straightforward with several splice variants, molecular ligands and possible modes of action most of which have only begun to be understood (113). Hence, a future challenge will be to sort out whether the role played by CTLA-4 in nTreg biology is as a suppressive mechanism, a route of activation or perhaps as a counterbalance to CD28 co-stimulation.


Figure 2
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  		Fig. 2 Possible suppressive mechanisms of Treg involving CTLA-4. The role of CTLA-4 in the suppressive mechanisms so far proposed offer a significant amount of different possibilities for regulation. (A) Treg might directly transmit a negative signal by CTLA-4 to CD80/86 expressed by effector T cells after TCR triggering. (B) Treg may induce indoleamine 2,3-dioxygenase production in DCs by CTLA-4 signaling which would lead to tryptophan degradation, generation of kynurenine and inhibition of T cell responses. (C) Ligation of CTLA-4 induces clustering formation by enhancing LFA-1–ICAM-1 interaction. The high expression of CTLA-4 on Treg could be favorable when interacting with DCs and cause alterations in DC/effector T cell priming or induce production of immunosuppressive metabolites. (D) An unexplored but intriguing possibility is that CD80/86 on APCs may signal through CTLA-4 on Treg that either enhance or maintain their suppressive function. Conceivably, more than one of these pathways may work in parallel. Of note, since CTLA-4 KO nTreg are suppressive in vitro, the molecule does not seem to be crucial for their suppressive function. However, this does not exclude that CTLA-4 still plays a significant role for Treg fitness and maintenance.

 
Interruption of suppression
For the full potential of an immune response to be reached, it is likely that nTreg suppression must be broken temporarily (Fig. 3). In favor of this notion, suppression by nTreg has been shown to be abrogated in culture with mature DCs or by signaling through CD28 or GITR (9, 114–116). Rather than a loss of function of nTreg, a major reason for the abrogation appears to be that effector T cells become refractory to suppression (105, 116). nTreg-mediated suppression is reversed in a similar fashion by the stimulation of DCs with CpG via Toll-like receptor (TLR) 9 and this was reported to be partly dependent on IL-6 production by DCs (117). Collectively, these findings again point to the DCs as being important in the making or breaking of suppression. Recent reports show that stimulation through TLR 2, 5 or 8 on nTreg is linked to modulation of nTreg function independently of APCs (118–120). Also, TLR 4 has been implicated in a similar manner, a finding that lately, however, has been challenged by other studies (118–121). Interestingly, MyD88 KO mice have significantly diminished numbers of nTreg which suggests a role for TLR signaling in nTreg homeostasis as well as for regulation of suppression (119). Thus, TLR stimulation during an infectious response may drive nTreg to extensive proliferation that, once PAMPs are cleared, endorse nTreg to regain immunological control and limit tissue destruction.


Figure 3
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  		Fig. 3 Interference with suppression. Activation of APCs through TLR 4 or TLR 8 may induce IL-6 production in combination with other immune stimulatory agents or mature their stimulatory function by up-regulation of CD86 and GITR ligand (GITRL). Effector T cells will bind these factors and become insensitive to nTreg suppression which is important for immunity. At the same time, PAMPs, such as lipoproteins, flagellin or nucleic acids, may interact directly with nTreg and abrogate suppression. TLR signaling and stimulation through CD28 and GITR can induce proliferation of nTreg which could be important for nTreg homeostasis and function.

 

   Concluding remarks
Top
 Abstract
 Introduction
 Treg taxonomy
 Thymic development of nTreg
 Peripheral development of murine...
 Suppressive mechanisms
 Concluding remarks
References
 
A striking feature of Treg is their fundamental role as guardians of tolerance and as such they hold much promise as targets of clinical therapy. The knowledge of Treg has grown enormously over the past decade and the emerging pattern is that of a both robust and flexible cell population which suppresses immunity by several distinct mechanisms. A recurring in vitro observation regarding means of suppression by nTreg is that one specific mechanism is never fully accountable for the failure of regulation. Indeed from an evolutionary point of view, it makes more sense to spread the risks by utilizing several different approaches. Still, it remains to be fully clarified if suppressive mechanisms observed in vitro can be transferred to the in vivo situation. Indeed, another puzzling question is how a small number of antigen-specific nTreg can keep immunity at bay and which suppressive mechanisms that entails. In this case, several things are important to consider such as the antigen specificity and the homing and migration properties of nTreg as well as the microenvironment in different organs of the body. One potential hypothesis is that nTreg basically share the homing and migratory pattern of conventional T cells but are constantly in a partially activated state ready for cell-to-cell interactions and are therefore easily triggered. It is possible that unless the steady state is broken by danger signals, one of the primary means of Treg function is to disarm APCs, thereby bringing any potentially harmful immune response to a halt before it begins. Finally, despite the fact that responder T cell responses are routinely used as read-outs of suppression, remarkably little is known about their fate during this process. To learn more about this could potentially straighten out some question marks and lead to a greater understanding of the dynamics of Treg-mediated suppression.


   Acknowledgements
 
The authors apologize to those researchers whose work, because of space restrictions, has not been cited. The authors thank their colleagues for allowing them to describe pre-publication material and acknowledge the helpful discussion with Tomoyuki Yamaguchi. The authors are funded by grants from Core Research for Evolutional Science and Technology and Astra-Zeneca.


   Abbreviations
 
APC, antigen-presenting cell
aTreg, adaptive regulatory T cells
DC, dendritic cell
GITR, glucorticoid-induced tumor necrosis factor family-related gene/protein
GvHD, graft versus host disease
KO, knockout
LFA-1, leukocyte function-associated antigen-1
nTreg, naturally occurring regulatory T cells
PAMP, pathogen-associated molecular pattern
TEC, thymic epithelial cell
TGF, transforming growth factor
TLR, Toll-like receptor
Tr1, T regulatory type 1
Treg, regulatory T cells
TSLP, thymic stromal lymphopoietin
Received 15 March 2006, accepted 19 April 2006.


   References
Top
 Abstract
 Introduction
 Treg taxonomy
 Thymic development of nTreg
 Peripheral development of murine...
 Suppressive mechanisms
 Concluding remarks
 References
 

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