Regulatory T cells overturned: the effectors fight back

Abstract

In the past 15 years, regulatory T cell (Treg) suppression has graduated from a phenomenon that ‘dare not speak its name’ to a field at the centre of a global research effort. It is now accepted that Tregs can target numerous cell populations to elicit potent immunosuppression. Intriguingly, emerging data suggest that certain signals can confer resistance to Treg suppression. Moreover, such resistance may be relevant to the pathogenesis of autoimmune diseases. In this article I review various pathways linked to resistance to Treg suppression. These include Toll-like receptor (TLR) signals, cytokines [in particular those that use the common γ chain, such as interleukin (IL)-7 and IL-21] and the triggering of tumour necrosis factor (TNF) receptor family members (such as glucocorticoid induced tumor necrosis factor receptor (GITR), OX40 and 4-1BB). I also propose a model of ‘tuned suppression’ in which inflammatory stimuli and TLR ligation actively promote Treg function, such that as soon as effector cells re-acquire sensitivity to suppression the immune response can be efficiently curtailed.

Introduction

Regulatory T cells (Tregs) are indispensable for the safe operation of the immune system. Their absence results in immune anarchy with devastating consequences for the host.^1,2 In addition to policing the activation of CD4 T cells it is now clear that Tregs can influence CD8 T cells^3,4 and B cells,^5,6 as well as cells of the innate immune system.^7,8 Thus Tregs enjoy far-reaching authority over diverse cellular constituents of the immune armoury. Given a degree of constitutive Treg activity in the steady state, consistent with their continuous stimulation by self antigen,^9,10 the Treg population could conceivably therefore present a barrier to effective immunity.

Interestingly, however, it has recently transpired that effector T cells are capable of acquiring resistance to Treg suppression. This scenario has now been reported in numerous animal models of autoimmunity, including diabetes models [both non-obese diabetic (NOD)^11,12 and DO11 x rip-mOVA¹³ mice], experimental autoimmune encephalomyelitis (EAE) models^14,15 and the MRL/Mp model of systemic lupus erythematosus (SLE).¹⁶ Importantly, the same trend is now emerging from human studies, in particular those relating to SLE patients.^17,18 The phenomenon of effector T cells resisting Treg suppression has prompted a shift in focus from how Tregs rule¹⁹ to how their jurisdiction can be overturned. An understanding of the mechanisms underlying this phenomenon will be critical for the optimal manipulation of Treg suppression in therapeutic settings.

Infection takes its toll: effect of Toll-like receptor (TLR) signalling on Treg suppression

An early indication of how Treg suppression might be overcome was provided by Medzhitov and colleagues.²⁰ Their experiments showed that TLR ligands such as lipopolysaccharide (LPS) and unmethylated CpG DNA motifs (which bind TLR-4 and TLR-9, respectively) permitted T cells to proliferate even in the presence of Tregs. This effect required dendritic cell (DC) MyD88 signalling and involved the production of soluble factors: thus supernatant from LPS-activated DCs abolished Treg suppression. Interleukin (IL)-6 appeared a likely player in these experiments, as neutralizing this cytokine partially abrogated the effects, although adding exogenous IL-6 failed to recapitulate them. This was interpreted to mean that IL-6 interrupted suppression by acting in concert with an additional factor whose identity remained unknown. Together these data supported a model in which ligation of pattern recognition receptors orchestrated a release from Treg control, allowing protective immunity to invading pathogens to proceed uninhibited.

Despite the teleological appeal of the above model, subsequent experiments suggest a more complex reality. Indeed, recent work has revealed that, in the context of malaria infection, TLR-9 triggering of DCs actually increases the number and suppressive capacity of Tregs.²¹ An important development in this field has been the realization that both conventional and regulatory T cells themselves express functional TLRs (reviewed in Refs ²² and ²³). Thus, in addition to eliciting cytokine production by DCs, the TLR ligands in the Medzhitov et al. study could themselves be acting directly on the T cells or Tregs. For example, it is now thought that CpG-DNA can directly costimulate T-cell proliferation²⁴ and, of particular note, can render T cells resistant to Treg suppression in a MyD88-dependent manner.²⁵ Ligation of TLR-2 has been reported to confer resistance to Treg suppression, in part by augmenting IL-2 production,²⁶ and this TLR can also signal Tregs directly, reducing their suppressive capacity.^26,27 Interestingly, curtailment of Treg function is only temporary; indeed, following a wave of TLR-2-driven proliferation, Treg suppression actually appeared to be enhanced.²⁷ A further study noted increased Treg function following TLR-2 engagement, in this case by the endogenous ligand heat shock protein 60 (hsp60).²⁸ Ligation of TLR-5 by flagellin has also been shown to increase Treg suppressive capacity²⁹ and some evidence suggests an equivalent function for LPS,³⁰ with a number of studies challenging the view that LPS abrogates Treg suppression.^29,31 In contrast, triggering of TLR-8, which like TLR-9 binds nucleic acid ligands, has been shown to directly impair Treg function.³¹

Thus, Treg suppression can be either boosted or thwarted by distinct TLR ligands. Regarding TLRs that signal directly to Tregs, it may be significant that the key players implicated in down-regulating Treg function (TLR-8 and TLR-9) are those that exhibit an intracellular distribution. One could speculate that the hijacking of Tregs by intracellular pathogens poses a sufficient threat, by permitting the potential for unfettered immunosuppression, to necessitate a dedicated safety mechanism; namely, that the sensing of nucleic acid ligands by endosome-expressed TLRs triggers Treg shut-down.

Effect of cytokines on Treg suppression: not the usual suspects…

Embedded in some of the original descriptions of the natural Treg population was the observation that IL-2 could abrogate suppression.^32–34 Subsequently, the influence of numerous cytokines on Treg suppression has been examined, and the results are summarized in Table 1. One limitation of the published literature is the frequent use of thymidine-incorporation assays that fail to distinguish between Treg and T-cell proliferation. In this regard, it is useful to note that the combination of IL-15 and IL-2 appears to break Treg anergy³⁵ while IL-6 and IL-1 greatly potentiate the Treg proliferative response to IL-2.³⁶ IL-4 also triggers Treg proliferation and this effect increases dramatically in co-culture with conventional T cells,^37,38 probably as a consequence of IL-2 availability. Thus, the capacity of these cytokines to abrogate suppression cannot be faithfully assessed in thymidine-incorporation assays, as concomitant proliferation of Tregs will confound the result.

Table 1.

Capacity of various cytokines to counteract regulatory T cell (Treg) suppression

Cytokine	Overcomes Treg suppression?
IL-1	Yes, but makes Tregs proliferate, reversed suppression of proliferation but not that of IL-2 production48
IL-2	Yes33 Yes, but makes Tregs proliferate32 Yes, but makes Tregs proliferate34 Yes, reversed suppression of proliferation but not that of IL-2 production40Yes39
IL-4	No39 Yes, reversed suppression of proliferation but not that of IL-2 production40 Yes, reversed suppression of proliferation but not that of IL-2 production38
IL-6	No39No31No (50 ng/ml)45 No, unless combined with an additional factor20 Partial effect (25 ng/ml) – yes in combination with TNF-α14 Yes (100 ng/ml): IL-6 blockade restored suppression when DCs were isolated from mouse model of lupus, but had no effect on suppression in presence of wild-type DCs102
IL-7	Yes, especially with IL-1539Yes45
IL-10	No39
IL-12	No39 Yes, reversed suppression of proliferation but not that of IL-2 production103
IL-13	No101
IL-15	Yes, especially with IL-739
IL-17	No14 No56
IL-18	Yes, reversed suppression of proliferation but not that of IL-2 production48
IL-21	Yes52 Yes13
IL-23	No103
TNF-α	No39No (5 ng/ml)47 No (25 ng/ml)13 No/minimal (100 ng/ml)48No/not significant (50 ng/ml)45 Partial effect (25 ng/ml) – yes in combination with IL-614 Yes (10 ng/ml) – but makes Tregs proliferate49Yes (50 ng/ml)46
TGF-β	No39
IFN-γ	No39 No14 No103

Data from human studies are shown in italics and those from mouse studies in plain font. The propensity of cytokines to make Tregs proliferate is indicated, as this can impact on assay interpretation. Dosing information is included for tumour necrosis factor (TNF)-α and interleukin (IL)-6 where available.

DC, dendritic cell; IFN, interferon; TGF, transforming growth factor.

IL-2

In respect of IL-2, experiments in which conventional T cells were labelled with carboxyfluorescein succinimidyl ester (CFSE), such that their proliferation could be analysed independently from that of the Tregs, confirmed its capacity to abrogate suppression.³⁹ Curiously, it has also been suggested that IL-2 can prime Treg function, effectively allowing T cells to solicit their own suppression.⁴⁰ The ability of IL-2 to up-regulate IL-10,⁴¹ CD25,⁴¹ cytotoxic T-lymphocyte antigen (CTLA-4)⁴² and forkhead box P3 (Foxp3)⁴³ may be important in this regard. At face value, a role for IL-2 in priming Treg function appears at odds with the established capacity of Tregs to suppress production of this cytokine. However, closer analysis reveals that Tregs do not completely veto IL-2 synthesis during co-culture with T cells.⁴¹ In fact, studies with IL-2-green fluorescent protein (GFP) mice suggest that T-cell IL-2 transcription and translation are virtually unaltered by the presence of Tregs during the first 2 days of stimulation.⁴⁴ Despite intact production of IL-2 in T cells co-cultured with Tregs, levels of this cytokine in the supernatant were vanishingly low,⁴⁴ probably reflecting consumption by Tregs.^41,44 The potential of Tregs to act as an IL-2 sink may explain why they are often purported to ‘suppress’ IL-2, even when their capacity to inhibit proliferation has been lost (Table 1). Taken together, the data imply a dual role for IL-2, suggesting that it can boost Treg function but also endow T cells with the capacity to escape suppression.

IL-6 and TNFα

Despite initial reports, it appears from the majority of studies that IL-6 alone is insufficient to overcome Treg suppression,^31,39,45 although such a function may emerge in combination with other factors (Table 1).^14,20 The capacity of TNF-α to counteract Treg suppression remains similarly controversial, with some reports that it does counteract suppression⁴⁶ and some that it doesn’t,^39,45,47,48 while still others suggest that it counteracts suppression but simultaneously enhances Treg function,⁴⁹ much like the scenario described for IL-2.

IL-7 and IL-15

CFSE-labelling studies by Sallusto and colleagues have uncovered a clear role for IL-7 and IL-15 in countering Treg suppression,³⁹ with IL-7 alone having a notable impact.^39,45 The mechanism is likely to involve the acquisition of T-cell resistance, as preincubation of Tregs with IL-7 and IL-15 has been shown to maintain their suppressive potential.⁵⁰ These observations are particularly pertinent in the light of the fact that IL-7 and IL-15 are elevated in the synovial fluid of individuals diagnosed with polyarticular juvenile idiopathic arthritis,³⁹ and suggest that this cytokine combination may be a physiologically important barrier to effective immune regulation. Intriguingly, IL-7 and IL-15 are the characteristic cytokines associated with lymphopenia, raising the possibility that Treg suppression is disabled in lymphopenic settings. This may be pertinent to the recognized association between lymphopenia and autoimmunity.⁵¹

IL-21

Interestingly, recent work has highlighted the potential for an additional IL-2 family member, IL-21, to overcome Treg suppression both in mice¹³ and humans.⁵² Levels of IL-21 were shown to increase in the pancreatic lymph nodes during progression to diabetes in the DO11 × rip-mOVA mouse model, coincident with the acquisition of resistance to Treg suppression.¹³ The emergence of resistance to Treg suppression is also a feature of diabetes in NOD mice,^11,12 which have been reported to overexpress IL-21,⁵³ although this overexpression of IL-21 remains controversial.⁵⁴ Nevertheless, the fact that IL-21-receptor-deficient NOD mice are protected from diabetes⁵⁴ implies that IL-21 is produced at physiologically relevant levels in the NOD strain, and places this cytokine in the frame for interrupting Treg suppression in spontaneous autoimmunity.

Thus, while re-analysis of a number of cytokines in more refined assays appears warranted, an emerging theme seems to be that cytokines that signal through the common γ chain (IL-2, IL-7, IL-15 and IL-21) may be particularly important in counteracting Treg suppression. If IL-2 scavenging constitutes at least a part of the Treg programme, perhaps generating a local environment conducive to suppression, substituting IL-2 with other family members could conceivably interfere with this.

Effect of TNF receptor (TNFR) family members on Treg suppression

GITR

Agonistic antibodies against the TNFR family member GITR have been shown to restore thymidine incorporation in T-cell:Treg co-cultures^55,56 and provision of GITR ligand (GITRL) on transfected cells⁵⁷ or in soluble form^58,59 recapitulates this effect. Tregs were pinpointed as the recipients of the GITR signal in elegant experiments in which mouse Tregs were used to suppress rat CD25− T cells, and proliferation was restored by mouse specific anti-GITR antibody.⁵⁵ Surprisingly, studies in which either T cells or Tregs were derived from GITR-deficient mice arrived at the opposite conclusion; expression of GITR was required on T cells (but not Tregs) for anti-GITR antibodies to restore proliferation in co-culture.⁵⁷ Crucially, it has now been established that GITR signalling can trigger Treg proliferation in the presence of IL-2,^56,58 raising the possibility that this could mask suppression in thymidine-incorporation assays. CFSE experiments in which anti-GITR antibodies could only target Tregs confirmed the increase in Treg proliferation but most intriguingly showed that this was associated with enhanced suppressive function.⁵⁷ These data argue that GITR signals actually increase Treg function but this is normally masked by a concomitant propensity to augment proliferation of both T cells and Tregs.

Of note, in a transplant model, GITR ligation compromised Treg-dependent tolerance but had no effect on the response of T cells alone.⁶⁰ The implication is that GITR acts on Tregs in this setting, although an effect on T cells that only manifests in the presence of Tregs cannot be formally ruled out. In this respect, the potential for GITR ligation to enhance IL-2 production⁵⁸ or protect from apoptosis⁶¹ could conceivably become relevant in the face of Treg competition for survival cytokines.⁴⁴

Taken together, the available data suggest that a major pathway by which GITR ligation counters Treg suppression is through the stimulation of conventional T cells and that GITR signals in Tregs may even enhance suppressive function. GITR therefore assumes a position amongst the list of agents that appear to augment the responses of both Tregs and T cells.

OX40

Attention has also turned to whether OX40 signalling can influence Treg suppression. APCs transfected with OX40 ligand (OX40L)^62,63 or agonistic anti-OX40 antibodies^62,63 have been shown to interrupt suppression, although evidence that naturally expressed OX40L plays an equivalent role is scant. Controversy surrounds which cell type represents the target for such effects; some reports suggest that OX40 triggering of Tregs alone is sufficient to negate suppression⁶² and others show that OX40 stimulation of both Tregs and T effectors is required,⁶⁴ while in a further report anti-OX40 antibodies were shown to abrogate suppression in a setting where T cells, but not Tregs, expressed OX40.⁶³ Curiously, Tregs isolated from OX40L transgenic animals showed enhanced suppressive function,⁶³ arguing against the idea that OX40 signals directly inhibit Treg function. While the role of OX40 in natural Tregs remains controversial, compelling evidence suggests that OX40 inhibits induction of adaptive Tregs;^62,64,65 accordingly, agonistic OX40 antibodies significantly reduce transforming growth factor (TGF)-β-mediated induction of Foxp3 in conventional CD4 T cells.⁶⁵ Thus the OX40 pathway could potentially promote immune responses both by conferring resistance to Treg suppression and by inhibiting Treg induction.

4-1BB

A further member of the TNF receptor family linked to the modulation of Treg suppression is 4-1BB. Provision of 4-1BB ligand abrogates Treg suppression in standard co-culture assays⁶⁶ and this is largely believed to reflect a role for 4-1BB signalling in rendering conventional T cells resistant to suppression rather than impairing Treg function.^67,68 Thus it appears that GITR, OX40 and 4-1BB can all counteract Treg suppression, although a detailed understanding of which cells these receptors act on, and the source of the relevant ligands, is currently lacking.

Intracellular signalling pathways linked to resistance to Treg suppression

Reports of resistance to Treg suppression in a number of gene-deficient animals can provide useful clues to the underlying mechanisms. A major breakthrough in this area came from analysis of mice lacking the E3 ubiquitin ligase Cbl-b, whose T cells were found to be completely refractory to Treg suppression.⁶⁹ These animals develop spontaneous autoimmunity characterized by autoantibody production and extensive tissue infiltration, consistent with a failure in immune regulation.⁷⁰ Tregs isolated from Cbl-b-deficient mice retained intact suppressive function,⁶⁹ laying the blame firmly at the feet of the conventional T cells. In a second example, T cells from animals double-deficient in NFATc2 and NFATc3 were shown to exhibit profound resistance to the effects of Tregs, although this time defects in the function of the Treg population were also identified.⁷¹ Finally, resistance to Treg suppression has also been described in TNF receptor associated factor 6 (TRAF6)-deficient mice, in which the Tregs themselves function normally.⁷² TRAF6 is a signalling adaptor that can transduce signals from both TNFR and IL-1/Toll-like receptor superfamilies and, like Cbl-b, can act as an E3 ubiquitin ligase.^73,74 The observation that phosphoinositide 3-kinase (PI3-kinase) activity is increased as a result of both Cbl-b and TRAF6 deficiency^72,75 prompted the hypothesis that activation of this pathway represents a unifying mechanism for conferring resistance to Treg suppression.⁷⁶ In proposing this hypothesis, Wohlfert and colleagues also highlighted the fact that T cells from both NFATc2/c3-deficient⁷⁷ and Cbl-b-deficient⁷⁰ mice can be activated in the absence of CD28 signals. Thus, resistance to T-cell suppression is associated with CD28-independent T-cell activation, consistent with elevated PI3-kinase activity. As IL-2,⁷⁸ IL-7⁷⁹ and IL-21,⁸⁰ as well as TLR ligands such as CpG,²⁴ have all been reported to activate PI3-kinase, this makes a mechanistic link between PI3-kinase signalling and resistance to Treg suppression even more plausible. Also, it should be noted that one of the first treatments shown to abrogate Treg suppression was provision of agonistic anti-CD28 antibody,³² a strategy that directly engages the PI3-kinase pathway.⁸¹

The notion that CD28-derived signals overcome Treg suppression assumes a new significance in the light of emerging data on the role of CTLA-4 in Treg function. Involvement of CTLA-4 in Treg suppression has been suspected for some time,^82–84 and recent data from Sakaguchi’s laboratory provide strong support for this idea.⁸⁵ Sakaguchi and colleages showed that deficiency of CTLA-4 only in Foxp3-expressing Tregs results in spontaneous lymphoproliferation and fatal T-cell-dependent autoimmune disease, reminiscent of the phenotype of mice lacking CTLA-4 systemically.^86,87 Thus, loss of CTLA-4 in Tregs alone is sufficient to allow fatal systemic autoimmunity. Complementary data from our own laboratory demonstrate that antigen-specific Tregs deficient in CTLA-4 are unable to control pancreatic islet autoimmunity.⁸⁸ Thus, CTLA-4 assumes its place in the list of effector mechanisms at the disposal of the Treg (reviewed in Refs ^89,90). Precisely how Treg-expressed CTLA-4 works to suppress immune responses remains to be elucidated. However, the fact that Tregs can down-regulate expression of the costimulatory ligands CD86 and CD80 on APCs in both mice^88,91,92 and humans (O. Qureshi and D. Sansom, University of Birmingham, Birmingham, UK, personal communication) suggests a model in which Tregs could use CTLA-4 to directly modify APCs. Significantly, suppressive mechanisms that rely on depletion of costimulatory ligands (CD86/CD80) would prove powerless to control T cells already endowed with the downstream consequences of CD28 signalling, as a result of either gene deficiency (Cbl-b, NFATc2/c3 or TRAF6) or cytokine supplementation.

Getting the right balance: a model of tuned suppression

At face value, it would appear that a bewildering array of signals are capable of counteracting Treg suppression. A recurrent theme in the literature is that treatments that counteract Treg suppression actually enhance Treg function if the Treg compartment is examined in isolation. This apparent paradox holds true for GITR,⁵⁷ OX40,⁶³ IL-2,⁴⁰ TNF-α,⁴⁹ and perhaps even some of the TLRs.³⁰

To reconcile these data, I propose a model of ‘tuned suppression’ in which infection and inflammation turn up the capacity of Tregs to suppress but T cells are not immediately receptive to their activity (Fig. 1). According to this model, Tregs do not arrest a primary immune response to an invading pathogen but instead use it to enhance their own representation and fitness. As the immune response emerges, Tregs track the effector T cells numerically, feeding off the very same signals as them and stealing the IL-2 they produce.⁹³ The ability of cytokines (including IL-1, IL-2, IL-4 and IL-6), TLR ligands, and potentially TNF receptor family members to drive Treg proliferation may be important in allowing Tregs to expand hand-in-hand with T cells. I propose that, far from being switched off, Treg function is actually enhanced during this phase. The notion that inflammation promotes Treg function is supported by the observation that Tregs from herpes simplex virus-infected⁹⁴ or malaria-infected²¹ mice, or Tregs derived from the inflamed central nervous system¹⁵ or pancreas¹³ exhibit augmented suppressive capacity. Despite heightened Treg function, the immune response is not stifled at this point as responder T cells acquire resistance to Treg suppression. It is noteworthy that the very first parameter demonstrated to influence Treg suppression was the strength of antigen-receptor signalling,^95,96 with high antigen doses effectively rendering T cells refractory to suppression. As a key feature of bacterial or viral infection is rapid multiplication resulting in an escalating infectious load, the high density of peptide–major histocompatibility complex (MHC) complexes available at this time-point could contribute to resistance. Add to that the effect of cytokines, TLR ligands and TNF ligands up-regulated on APCs and T cells during activation, and it is easy to envisage how T cells are rendered refractory to suppression.

Figure 1.

Model of tuned suppression: an immune response ‘primes’ the regulation required for its safe resolution. (a) High antigen dose, Toll-like receptor (TLR) ligation, cytokines and costimulation confer resistance to regulatory T cell (Treg) suppression in the context of infection. Many of these signals concomitantly enhance Treg suppression but their effects are largely resisted at this juncture. (b) As the pathogen load falls, the decreased density of presented antigen and loss of TLR-induced signals allow susceptibility to Treg suppression to be restored. The augmented Treg function conferred by proliferation and immune stimulation in (a) comes into play at this point to ensure efficient termination of the immune response. DC, dendritic cell; MHC, major histocompatibility complex; TNF, tumour necrosis factor.

Although controversy exists over whether Tregs can suppress at the same time as dividing, there is a strong consensus that following proliferation their function is markedly enhanced.^{30,56,97–99} This has been shown to hold true when proliferation is induced in ‘inflammatory’ settings including in the context of ligation of certain TLRs.^27,30 According to the ‘tuned suppression’ model, the potential of expanded Tregs to elicit increased suppression is only realized once the pathogen load has been reduced. Lower antigen doses favour susceptibility to Treg suppression;^95,96 indeed, it has been known for a decade that the strength of TCR signalling required to induce Tregs to suppress is significantly lower than that required to trigger proliferation of conventional T cells.³² A decreased pathogenic load also equates to less TLR engagement, such that a further mechanism for conferring resistance to Treg suppression is now removed. TLR-triggered production of cytokines from APCs will wane, and expression of costimulatory ligands will drop into the range where suppressive mechanisms invoking ligand competition can come into play. The combined effect of these changes is that T-cell susceptibility to Treg suppression will be reinstated; importantly, the enhanced suppressive capacity of the Tregs on a per cell basis ensures their dominance at this point. The remit of the Treg population in this phase encompasses dampening of the innate^7,100 as well as the adaptive immune system, thereby breaking the positive feedback cycles that amplify, diversify and perpetuate immune responses. Limiting the capacity of the immune response to spread to new epitopes has obvious relevance to the prevention of autoimmunity. However, in the context of an autoimmune response, the failure of antigen clearance, and persistence of cytokine production, could contribute to the long-term resistance to Treg suppression that has been observed in this setting.

It is worth noting that many of the signals regulating Treg homeostasis and function in such a model are essentially antigen independent, many being soluble mediators. Thus, while the Tregs could be pathogen-specific in this setting, it is also plausible that the homeostasis and function of Treg responding to local self antigens are positively regulated by infection. In this regard, very recent work suggests that, during response to immunized antigen, the entire local Treg population shows rapid evidence of IL-2 signalling [H. Dooms, W. O’Gorman and A. Abbas, University of California San Francisco (UCSF), San Francisco, CA, personal communication].

Conclusion

It is clear that multiple signals can confer resistance to Treg suppression and these may share a common mechanistic basis. I propose that, during an immune response, T-cell resistance to suppression and enhanced Treg function are acquired hand-in-hand, largely driven by similar signals. Resistance to suppression gives the effector response freedom to generate protective immunity when it counts, but ‘tuned-up’ Treg function gives regulatory mechanisms the upper hand following pathogen clearance.

The long-standing search for signals that turn off Tregs has yielded relatively few definitive insights; instead, recent data suggest that resistance of effector T cells to Treg suppression may ultimately prove more relevant. Defining the mechanistic basis of this phenomenon will advance our understanding of the pathogenicity of autoimmunity and facilitate the optimization of Treg cell-therapy strategies.

Disclosure

None.