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Nat Rev Rheumatol. Author manuscript; available in PMC May 3, 2011.
Published in final edited form as:
PMCID: PMC3086064

Regulatory T cells as therapeutic targets in rheumatoid arthritis


Regulatory T cells (TREG) are a subset of CD4+ T cells with a critical role in the prevention of autoimmunity. Whether defects in TREG contribute to the pathogenesis of rheumatoid arthritis (RA) is unclear. However, a variety of approved and experimental drugs for RA may work, in part, by promoting the function or increasing numbers of TREG. Furthermore, animal studies demonstrate that direct injection of TREG ameliorates a wide range of experimental models of inflammatory and autoimmune diseases. Thus, cell-based therapy with TREG has the potential to produce durable disease remission in patients with RA.


The ultimate goal of therapy for patients with active rheumatoid arthritis (RA) and other autoimmune diseases is to restore normal immune function rather than to achieve broad immunosuppression. Evidence has accumulated over the past decade that regulatory T cells (TREG) could be an ideal target for therapies to induce durable remission of autoimmune and inflammatory disease (reviewed elsewhere1). TREG are ideal for this purpose because they suppress inflammation in an antigen-specific manner. Furthermore, short-term therapy with TREG can lead to long-term inhibition of autoimmune disease in mouse models, and immunomodulatory agents can affect numbers and functioning of TREG in both mice and humans. Thus, approaches that bolster numbers or functioning of TREG could achieve selective and durable inhibition of pathologic inflammation without blocking protective immune responses against infection. In this Review, we discuss the use of small-molecule drugs, biological agents and direct TREG administration to increase numbers or promote the functions of TREG and to interrupt chronic inflammation in patients with RA (Figure 1).

Figure 1
Effects on TREG of various therapies for RA. Several immunomodulatory agents that are or may be effective in the treatment of RA boost numbers or function of TREG. Cytokine-based therapies, such as IL-2 (aldesleukin) or agents that block TNF or the IL-6 ...

TREG constitute 5–7% of CD4+ T cells in humans.2,3 These regulatory cells suppress immune responses through a variety of contact-dependent and contact-independent mechanisms.4,5 Importantly, they have an inherently autoreactive T cell receptor (TCR) repertoire, and antigen recognition through the TCR is required to suppress immune responses.1,6 The transcription factor forkhead box P3 (FOXP3) is critical for the generation and peripheral maintenance of TREG in both mice7 and humans.8 Mutations in FOXP3 or its regulatory regions cause an X-linked syndrome of immune dysregulation, polyendocrinopathy and enteropathy (IPEX) characterized by massive polyclonal T cell activation and tissue in filtration.811 Immune homeostasis in patients with IPEX can be successfully restored with hematopoietic stem cell transplantation following submyeloablative conditioning, since TREG exert a dominant regulatory effect that prevents systemic T cell activation and autoimmunity.10,1214 Moreover, other genetic loci that encode molecules involved in TREG function have been linked to autoimmunity in genome-wide association studies.15 Together, these observations have spurred further work on TREG in patients with common polygenic autoimmune diseases.

Three problems limit the use of FOXP3 expression alone to study TREG in humans. First, FOXP3 is expressed transiently in most activated human T cells, often without conferring a regulatory phenotype.16,17 Furthermore, cells that are both FOXP3+ and immunosuppressive may lose this suppressive capacity under certain conditions.18,19 Second, recent mouse studies have shown that DNA methylation status at the Foxp3 locus may be a better marker of a stable TREG phenotype than FOXP3 protein expression.18,20 Third, FOXP3 is an intracellular protein that cannot be used to isolate TREG for functional studies. Thus, in practice, assessments of TREG function in patients with autoimmune diseases must rely on use of cell surface markers to identify and isolate TREG for in vitro studies. Although many cell surface proteins are differentially expressed on TREG,21 no known cell surface markers are expressed exclusively on TREG. In fact, research on cells identified as TREG has been complicated by the early use of only CD4 and CD25 expression to identify these cells. CD4+ T cells that express high levels of CD25 (CD4+CD25high cells) are generally FOXP3+ and highly immunosuppressive.22 However, the CD4+CD25high population also includes effector T cells.23 This contamination has, in some cases, misled investigators to believe that deficits in TREG function exist where they do not. The best approach, therefore, is to use a constellation of cell surface markers, including folate receptor 4, IL-7 receptor subunit α (CD127), latency-associated peptide (LAP), and glucocorticoid-induced TNF receptor-related gene (GITR) to isolate TREG and study their function.21 For instance, our group showed that low levels of CD127 expression in combination with CD4 and CD25 expression can identify more than 95% of FOXP3+ T cells that have highly immunosuppressive activity.2

Are TREG defective in RA?

Whether TREG defects are present in patients with RA is not clear. One study reported that the number of CD4+CD25high TREG in the peripheral blood of patients with RA is elevated as compared with that of healthy individuals,24 whereas other studies suggest no differences in peripheral blood TREG numbers between these two groups.2527 Several studies have reported that CD4+CD25high T cells are present in the synovial fluid of patients with RA and that their function is normal in vitro.24,26,28,29 However, these in vitro assays are not antigen-specific and the accumulation of polyclonal TREG in inflamed tissues might be a general phenomenon.30,31 Thus, a critical question is whether numbers of antigen-specific TREG differ in healthy and affected individuals.

Two groups have reported that peripheral blood TREG isolated from patients with RA and from control individuals showed no difference in their ability to suppress effector T cell proliferation.24,25 However, another group reported a striking defect in the capacity of TREG from patients with RA to suppress effector T cell proliferation.32 These divergent results could reflect differences in the populations of patients, the methods used to purify TREG, or how the suppression assays were performed. Some evidence suggests that TREG from RA patients are defective in their ability to suppress the production of two principal proinflammatory cytokines—interferon (IFN)-γ and tumor necrosis factor (TNF)—by effector T cells.25 This defect is associated with decreased surface expression of cytotoxic T-lymphocyte antigen 4 (CTLA-4) on TREG and can be reversed by increasing CTLA-4 expression with phorbol ester treatment in vitro.27 Importantly, effector T cells can become resistant to suppression by TREG in patients with autoimmune disease, and this observation can influence interpretation of the above results.33 Overall, whether the reported defects in TREG function in patients with RA are the cause or result of chronic inflammation is not yet clear.

Effects of approved drugs on TREG

Although much still remains to be clarified about how TREG defects might contribute to the pathogenesis of RA, approaches that specifically boost TREG activity could be useful in the treatment of RA. High concentrations of TNF can block the immunosuppressive functions of TREG in vitro.32 In this context, a notable observation is that treatment of RA patients with anti-TNF drugs bolsters TREG suppression of proinflammatory cytokine production.25 For example, infliximab treatment restores the ability of TREG to suppress the production of IFN-γ and TNF by effector T cells, an effect that could be attribut able to either improved TREG function or increased sensitivity of effector T cells to such suppression. However, several additional findings suggest that TNF has direct effects on TREG that can be inhibited by infliximab. First, restoration of TREG function was accompanied by increased numbers of CD4+CD25high T cells in the blood of patients after anti-TNF treatment. Second, further work from the same group showed that these cells are induced TREG that express low levels of L-selectin (CD62L) and suppress effector cell cytokine production via transforming growth factor β and IL-10.34 Finally, anti-TNF treatment decreased expression of TNF receptor 2 and GITR, and increased FOXP3 expression, within the CD4+CD25high population.32

Key points

  • ■ FOXP3+ regulatory T cells (TREG) control autoimmunity in humans
  • ■ Some evidence suggests that patients with rheumatoid arthritis have defects in TREG, but whether these defects are the cause or result of chronic inflammation is not clear
  • ■ Several approved and experimental drugs promote function or increase numbers of TREG, and these effects may be responsible for these drugs’ efficacy in treating RA
  • ■ Cellular therapy with autologous ex vivo expanded TREG may prove effective as a treatment for patients with RA

Tocilizumab, an antibody that blocks the human IL-6 receptor, has shown efficacy in the treatment of RA3538 and has been approved by European regulators for this indication. IL-6 is a proinflammatory cytokine produced by a variety of hematopoietic cells, including dendritic cells. IL-6 can block the immunosuppressive activity of TREG in mice.39 By contrast, blockade of the IL-6 receptor with a monoclonal antibody in mice attenuates the severity of graft-versus-host disease and increases the absolute number of TREG in the spleens of treated mice through conversion of peripheral CD4+ T cells to TREG.40 IL-6 prevents FOXP3 upregulation in human T cells in vitro.41,42 Thus, blockade of the IL-6 receptor may benefit patients with RA, at least in part, through augmenting the conversion of peripheral effector T cells to TREG, perhaps by preventing IL-6 from driving CD4+ cells toward a type 17 T-helper cell (TH17) phenotype.43 Importantly, IL-6 reportedly has no effect on the immunosuppressive capacity of TREG from the synovial fluid of patients with RA.44 More work needs to be done, therefore, to elucidate the effects of IL-6 receptor blockade on the balance between TREG and TH17 differentiation.

Another drug class that may affect TREG function in patients with RA includes the FDA-approved CD28 co-stimulation blocker, abatacept (a CTLA4–Ig fusion protein), and its higher-affinity derivative, belatacept. These drugs bind to the CD28 ligands CD80 and CD86 with a higher affinity than does the CD28 receptor, which prevents T-cell co-stimulation and interferes with T-cell-driven autoimmune processes.45 Long-term belatacept treatment as part of an immunosuppressive regimen after kidney transplant had no effect on the percentage of circulating CD4+FOXP3+ T cells but increased the percentage of FOXP3+ T cells in biopsy samples from kidneys undergoing acute rejection.46 However, in mice, complete blockade of CD28 binding to CD80 and CD86 results in a precipitous loss of TREG.47 These apparently contradictory results are probably related to the subsaturating doses of belatacept that were used in the human studies,46 which resulted in selective loss of effector T cells and an increased proportion of TREG in inflamed tissue.48,49 Determining the optimal dose of CTLA4–Ig in patients with RA and other diseases will be critical if effector T cells are to be selectively inhibited while TREG function is preserved.

Rapamycin is an immunosuppressive small-molecule drug with a wide variety of effects on cells of both the innate and adaptive immune systems.50 Importantly, rapamycin and other mTOR (mammalian target of rapamycin) inhibitors promote human TREG survival and differentiation and block effector T cell proliferation.51,52 Patients with RA who were treated with both the rapamycin derivative, everolimus, and methotrexate showed a greater response rate than patients treated with methotrexate alone. Thus, mTOR inhibition may ameliorate autoimmunity in part by promoting TREG function. However, to what extent the clinical efficacy of rapamycin results from its effects on TREG is not known.

Experimental drugs that affect TREG

Toll-like receptors (TLRs) are expressed on cells of the immune system and respond to the presence of microbial products as well as to human self-molecules such as RNA and DNA.53 TREG express multiple TLRs, and different TLR ligands regulate the immunosuppressive capacity of murine TREG in vitro and in vivo (reviewed elsewhere54,55). Mice deficient in TLR9 have elevated numbers of TREG in gut-associated lymphoid tissue, which highlights the importance of TLRs to TREG homeostasis.56 Furthermore, synovial fluid from patients with RA contains TLR3 ligands, which promote inflammatory cytokine production in RA synovial fibroblasts.57 In fact, hydroxychloroquine, a drug currently used to treat RA, may work in part by blocking TLR signaling.58 IRS 954, an experimental antagonist of TLR7 and TLR9, reduces titers of antibodies to antinuclear antigens and decreases glomerulonephritis in lupus-prone (NZB × NZw F1) mice.59 These results suggest that TLR antagonists could have therapeutic effects in patients with RA as a result of directly or indirectly boosting TREG function.

Trichostatin A is a small-molecule inhibitor of histone deacetlyases (HDACs) that increases numbers of TREG in normal mice by increasing thymic output of TREG.60 A recent study demonstrated that the HDAC inhibitors MS-275 and vorinostat (suberoylanilide hydroxamic acid) induce FOXP3 expression and immunosuppressive capacity in human T cells activated in vitro.61 Trichostatin A may work by increasing the acetylation and functioning of FOXP3,60 or by preventing TREG from producing IL-17.62 Thus, promotion of TREG differentiation might be a general result of HDAC inhibition, which suggests that HDAC inhibitors may, in future, have a role in therapy for autoimmune and inflammatory diseases. One HDAC inhibitor, vorinostat, has been approved by the FDA for the treatment of cutaneous T cell lymphoma,63 and could be tested in patients with autoimmune disease.

IL-2 is a principal survival factor for TREG64 and, in mice, its absence may contribute to defective TREG function in inflamed tissues.31 Mice treated with a stabilized form of IL-2 demonstrate increased TREG proliferation and function.31,65 IL-2, also known as aldesleukin, is currently used in cancer therapy, and some evidence suggests that it might also boost TREG numbers in humans.66 Thus, administration of IL-2 could prove useful in the treatment of human autoimmune disease.

Cellular therapy moving to the clinic

First attempts to use cell-based approaches as therapy for inflammatory arthritis involved hematopoietic stem cell transplantation (HSCT) to treat active, destructive, refractory RA6769 and juvenile idiopathic arthritis.70,71 Although this treatment was curative for some patients, prolonged immunosuppression after HSCT was associated with a significant risk of infection, which limited the potential of this therapy.72 However, data from these trials implicated TREG as a critical component of the regulatory state of the newly reconstituted immune system after transplant. In patients with juvenile idiopathic arthritis treated with HSCT, post-transplant reconstitution of CD4+CD25high TREG was more rapid than that of CD4+CD25 cells. This preferential recovery of TREG could result from the relative resistance of TREG to apoptosis after genotoxic stress.73 These results imply that other approaches to shifting the balance of the immune system away from inflammation and toward regulation, for example those that selectively bolster TREG numbers or function, could prove to be successful and less risky than HSCT.

One approach to boost numbers of TREG without myeloablative conditioning is to isolate TREG from patients, expand them in culture, and then re-infuse the cells.74 Since TREG are only a small fraction of peripheral CD4+ T cells (5–7%), the most effective approach to TREG-based immunotherapy will require in vitro expansion of natural TREG under carefully controlled conditions to ensure the preservation of their regulatory capacity.3,75Ex vivo TREG expansion and re-infusion has successfully prevented or reversed a number of autoimmune diseases in mouse models, including models of inflammatory arthritis.7680 In the future, several new techniques may be incorporated into TREG-based immunotherapies to improve the efficacy and safety of this approach. For example, TREG may be targeted to inflamed tissues by transducing polyclonal TREG with antigen-specific T cell receptors, an approach previously used to modify effector T cells used in cancer immunotherapy.81 Alternatively, antigen-specific TREG could be selected from a polyclonal population by stimulation with relevant peptides.82

Pitfalls of cellular therapy

Several pitfalls are possible in the treatment of patients with TREG. First, incomplete lineage commitment enables some human CD4+FOXP3+ cells to express nuclear factor ROR-γt and to develop into IL-17-producing effector cells.62,83,84 Moreover, recent data from mice suggest that some fully differentiated TREG may be unstable and able to trans-differentiate in vivo into effector memory T cells that produce pathogenic cytokines such as IFN-γ and IL-17.95 Contamination of therapeutic TREG with these unstable TREG, or even with true autoreactive effector T cells, could lead to exacerbation rather than attenuation of the autoimmune process. Second, TREG may be less effective in suppressing effector T cells in an autoimmune setting, and may even augment IL-17 production in vitro.86,87 Third, it is unclear whether a large polyclonal population of TREG would be able to interrupt an autoimmune process that targets antigens found in specific tissues. Fourth, polyclonal TREG therapy could result in generalized immunosuppression and increased susceptibility to infection. Finally, some patients with autoimmune disease may have poorly appreciated intrinsic defects in TREG function that cannot be overcome by infusion of large numbers of these defective cells. In spite of these potential concerns, however, clinical trials are underway to test the therapeutic potential of TREG in graft-versus-host disease.91,92


Although existing drugs significantly reduce the morbidity and mortality associated with RA, these therapies are not curative. Several drugs that affect TREG numbers or function have shown efficacy in the treatment of RA. These results imply that direct administration of TREG could be an ideal therapy to induce durable remission of RA, as these cells persist in vivo and act in an antigen-specific manner. Thus, approaches that bolster TREG numbers and functions could be a fruitful means of selectively and durably inhibit ing pathologic inflammation without blocking pr otective immune responses against infection.

Review criteria

Papers cited in this Review were identified by searching the PubMed database using the search terms “TREG” and “rheumatoid arthritis” and by using the reference lists from those papers to identify other relevant publications. Additional papers were suggested by colleagues or identified by searching PubMed using specific terms relevant to the various topics discussed in this Review. The reference list was last updated in July 2009.


The authors thank Todd Brusko and Amy Putnam for helpful discussions and for assistance with figure design.


Competing interests

The authors declare no competing interests.


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