Regulation of CD4+CD25+ regulatory T cell activity: it takes (IL-)two to tango

Although CD4(+)CD25(+) regulatory T cells (Treg) represent a well-characterized population of T cells with in vitro and in vivo suppressive capacity, the basic mechanisms of suppression are still not understood. The constitutive expression of the high-affinity receptor for IL-2 has raised the question about the role of IL-2 in Treg function. Here, we review recent data indicating that IL-2 is not only necessary for the homeostasis of Treg but is also critical for the activation of Treg function. Since Treg do not produce IL-2 by themselves, their capacity to utilize IL-2 secreted by other T cells appears to be an essential component of Treg biology. This indicates that Treg suppressive activity is controlled by interaction with activated target cells via the soluble mediator IL-2. In Treg, IL-2 has been identified as a potent inducer of the immunosuppressive cytokine IL-10, an important mediator of Treg suppression in vivo. The efficient capture of IL-2 by Treg may, under conditions of limited IL-2 supply, cause IL-2 deprivation of responder T cells. This competition can explain some of the currently discussed discrepancies between in vivo and in vitro activity of Treg.     

CD4+ Foxp3+ regulatory T cells mediate Toxoplasma gondii-induced T-cell suppression through an IL-2-related mechanism but independently of IL-10

Acute Toxoplasma gondii infection comprises an immunosuppression stage, characterized by a reduction in T-cell proliferation in vitro. Treg cells maintain the homeostasis of the immune system, but their role in T. gondii-induced suppression has not been addressed. We show herein that immunosuppression, affecting both CD4(+) and CD8(+) T-cell proliferation, concurs with a reduction in Treg-cell number. The residual Treg cells, however, are activated and display an increased suppressive capacity. We show that selective elimination of Treg cells using Foxp3(EGFP) mice leads to a full recovery of CD4(+) and CD8(+) T-cell proliferation. After Treg-cell removal, a reduced production of IL-10 was observed, but IL-2 levels were unchanged. The numbers of IL-10-producing Treg cells also increased during infection, although the in vitro neutralization of this cytokine did not modify T-cell proliferation, suggesting that IL-10 does not mediate the Treg-mediated suppression. However, addition of rIL-2 in vitro fully restored T-cell proliferation from infected animals. Thus, we show that Treg cells mediate the T-cell suppression observed during acute T. gondii infection through an IL-2-dependent mechanism. Our results provide novel insights into the regulation of the immune response against T. gondii.     

IL-2 induces in vivo suppression by CD4(+)CD25(+)Foxp3(+) regulatory T cells

Interleukin-2 (IL-2) treatment is currently used to enhance T cell-mediated immune responses against tumors or in viral infections. At the same time, IL-2 is essential for the peripheral homeostasis of CD4(+)CD25(+)Foxp3(+ )regulatory T cells (Treg). In our study, we show that IL-2 is also an important activator of Treg suppressive activity in vivo. IL-2 treatment induces Treg expansion as well as IL-10 production and increases their suppressive potential in vitro. Importantly, in vivo application of IL-2 via gene-gun vaccination using IL-2 encoding DNA plasmids (pIL-2) inhibited naive antigen-specific T cell proliferation as well as a Th1-induced delayed type hypersensitivity response. The suppressive effect can be transferred onto naive animals by Treg from IL-2-treated mice and the suppression depends on the synergistic action of IL-10 and TGF-beta. These data highlight that during therapeutic treatment with IL-2 the concomitant activation of Treg may indeed counteract the intended activation of cellular immunity.     

Distinct roles of CTLA-4 and TGF-beta in CD4+CD25+ regulatory T cell function

Both CTLA-4 and TGF-beta have been implicated in suppression by CD4+CD25+ regulatory T cells (Treg). In this study, the relationship between CTLA-4 and TGF-beta in Treg function was examined. Blocking CTLA-4 on wild-type Treg abrogated their suppressive activity in vitro, whereas neutralizing TGF-beta had no effect, supporting a TGF-beta-independent role for CTLA-4 in Treg-mediated suppression in vitro. In CTLA-4-deficient mice, Treg development and homeostasis was normal. Moreover, Treg from CTLA-4-deficient mice exhibited uncompromised suppressive activity in vitro. These CTLA-4-deficient Treg expressed increased levels of the suppressive cytokines IL-10 and TGF-beta, and in vitro suppression mediated by CTLA-4(-/-) Treg was markedly reduced by neutralizing TGF-beta, suggesting that CTLA-4-deficient Treg develop a compensatory suppressive mechanism through CTLA-4-independent production of TGF-beta. Together, these data suggest that CTLA-4 regulates Treg function by two distinct mechanisms, one during functional development of Treg and the other during the effector phase, when the CTLA-4 signaling pathway is required for suppression. These results help explain contradictions in the literature and support the existence of functionally distinct Treg.     

A clonal model for human CD8+ regulatory T cells: unrestricted contact-dependent killing of activated CD4+ T cells

Previous studies in murine systems have demonstrated that CD8(+) Treg cells down-regulate immune responses in vivo through suppressing activated CD4(+) T cells. Here we describe novel regulatory CD8(+) T-cell clones isolated from healthy human peripheral blood following in vitro stimulation with autologous Epstein-Barr virus (EBV)-specific CD4(+) T cells. TCR activation of CD4(+) target T cells was required for CD8(+) Treg cells to exert suppressive activity, which was mediated through lysis of CD4(+) targets in a cell contact-dependent manner. Suppression was independent of Foxp3 expression in CD8(+) Treg cells, HLA compatibility between CD8(+) Treg cells and CD4(+) target cells and antigen-specificity of CD4(+) target T cells. CD8(+) Treg clones expressed CD3 and a variety of TCR V(β) chains as well as CD56, CD69, CD62L and CD95 but did not express CD16, CD161, CXCR4 and CCR7. When used together, antibodies specific for CD11a/CD18 and CD8 inhibited suppressive activity of CD8(+) Treg clones. The ability to establish clonal CD8(+) T cells that maintain regulatory function in vitro will facilitate further studies to define this population in vivo and to identify the mechanisms used for recognition and suppression of activated target cells.     

CD4+ CD25+ [corrected] regulatory T cells render naive CD4+ CD25- T cells anergic and suppressive

CD4(+) CD25(+) Foxp3(+) naturally occurring regulatory T cells (nTreg) are potent inhibitors of almost all immune responses. However, it is unclear how this minor population of cells is capable of exerting its powerful suppressor effects. To determine whether nTreg mediate part of their suppressor function by rendering naive T cells anergic or by converting them to the suppressor phenotype, we cocultured mouse nTreg with naive CD4(+) CD25(-) T cells from T-cell receptor (TCR) transgenic mice on a RAG deficient (RAG(-/-)) background in the presence of anti-CD3 and interleukin-4 (IL-4) to promote cell viability. Two distinct responder cell populations could be recovered from the cocultures. One population remained undivided in the coculture and was non-responsive to restimulation with anti-CD3 or exogenous IL-2, and could not up-regulate IL-2 mRNA or CD25 expression upon TCR restimulation. Those responder cells that had divided in the coculture were anergic to restimulation with anti-CD3 but responded to restimulation with IL-2. The undivided population was capable of suppressing the response of fresh CD4(+) CD25(-) T cells and CD8(+) T cells, while the divided population was only marginally suppressive. Although cell contact between the induced regulatory T cell (iTreg) and the responders was required for suppression to be observed, anti-transforming growth factor-beta partially abrogated their suppressive function. The iTreg did not express Foxp3. Therefore nTreg are not only able to suppress immune responses by inhibiting cytokine production by CD4(+) CD25(-) responder cells, but also appear to modulate the responder cells to render them both anergic and suppressive.     

Critical role of IL-2 and TGF-beta in generation, function and stabilization of Foxp3+CD4+ Treg

CD4+Foxp3+ Treg consist of two indistinguishable subsets induced in either the thymus or the periphery. In addition to their suppressive activities, IL-6 can convert natural Treg to pro-inflammatory IL-17-producing cells, but those induced with IL-2 and TGF-beta remain Treg. Unlike mouse CD4+CD25(-) cells, which rapidly become polyclonal Foxp3+CD25+ Treg when activated appropriately with IL-2 and TGF-beta, human T cells require multiple stimulations to become similar suppressor cells.     

Natural Tregs, CD4+CD25+ inhibitory hybridomas, and their cell contact dependent suppression

The natural CD4+CD25+ T regulatory (Treg) lymphocyte has emerged as a critical cell for controlling immune responses to self, foreign proteins, and pathogens. Identified initially by the constitutive expression of CD4 and CD25, natural Tregs suppress a variety of immune cells and responses, including CD4+CD25− proliferation and IL-2 production, and CD8 cell proliferation, IFNγ production and CTL activity. Although natural Tregs require activation with specific antigen to attain their suppressive phenotype, once activated they execute inhibition in an antigen specific as well as non-specific (bystander) fashion. Treg suppression depends on IL-2, CD25, and cell:cell contact. The use of live cell imaging in vivo and in vitro to visualize the dynamic cell:cell interactions involving natural Tregs as well as the CD4+CD25+ Treg inhibitory hybridoma RD6 has refined the mechanistic models of contact dependent Treg suppression.     

CD25+ CD4+ T cells compete with naive CD4+ T cells for IL-2 and exploit it for the induction of IL-10 production

Maintenance of homeostasis in the immune system involves competition for resources between T lymphocytes, which avoids the development of immune pathology seen in lymphopenic mice. CD25+ CD4+ T cells are important for homeostasis, but there is as yet no consensus on their mechanisms of action. Although CD25+ CD4+ T cells cause substantial down-regulation of IL-2 mRNA in responder T cells in an in vitro co-culture system, the presence of IL-protein can be demonstrated by intracellular staining. As a consequence of competition for IL-2, CD25+ CD4+ T cells further up-regulate the IL-2R alpha chain (CD25), a process that is strictly dependent on IL-2, whereas responder T cells fail to up-regulate CD25. Similarly, adoptive transfer into lymphopenic mice showed that CD25+ CD4+ T cells interfere with CD25 up-regulation on co-transferred naive T cells, while increasing their own CD25 levels. IL-2 sequestration by CD25+ CD4+ T cells is not a passive phenomenon but instead initiates--in conjunction with signals through the TCR--their differentiation to IL-10 production. Although IL-10 is not required for in vitro suppression, it is vital for the in vivo function of regulatory T cells. Our data provide a link explaining the apparent difference in regulatory mechanisms in vitro and in vivo.     

Daily subcutaneous injections of peptide induce CD4+ CD25+ T regulatory cells

Peptide immunotherapy is being explored to modulate varied disease states; however, the mechanism of action remains poorly understood. In this study, we investigated the ability of a subcutaneous peptide immunization schedule to induce of CD4(+) CD25(+) T regulatory cells. DO11.10 T cell receptor (TCR) transgenic mice on a Rag 2(-/-) background were injected subcutaneously with varied doses of purified ovalbumin (OVA(323-339)) peptide daily for 16 days. While these mice have no CD4(+) CD25(+) T regulatory cells, following this injection schedule up to 30% of the CD4(+) cells were found to express CD25. Real-time quantitative polymerase chain reaction (QPCR) analysis of the induced CD4(+) CD25(+) T cells revealed increased expression of forkhead box P3 (FoxP3), suggesting that these cells may have a regulatory function. Proliferation and suppression assays in vitro utilizing the induced CD4(+) CD25(+) T cells revealed a profound anergic phenotype in addition to potent suppressive capability. Importantly, co-injection of the induced CD4(+) CD25(+) T cells with 5,6-carboxy-succinimidyl-fluorescence-ester (CFSE)-labelled naive CD4(+) T cells (responder cells) into BALB/c recipient mice reduced proliferation and differentiation of the responder cells in response to challenge with OVA(323-339) peptide plus adjuvant. We conclude that repeated subcutaneous exposure to low-dose peptide leads to de novo induction of CD4(+) CD25(+) FoxP3(+) T regulatory cells with potent in vitro and in vivo suppressive capability, thereby suggesting that one mechanism of peptide immunotherapy appears to be induction of CD4(+) CD25(+) Foxp3(+) T regulatory cells.     

CD4+ CD25+ regulatory T cells suppress contact hypersensitivity reactions by blocking influx of effector T cells into inflamed tissue

CD4+ CD25+ regulatory T cells (Treg) exert suppressive functions on effector T cells in vitro and in vivo. However, the exact cellular events that mediate this inhibitory action remain largely unclear. To elucidate these events, we used intravital microscopy in a model of contact hypersensitivity (CHS) and visualized the leukocyte-endothelium interaction at the site of antigen challenge in awake C57BL/6 mice. Injection of Treg i.v. into sensitized mice at the time of local hapten challenge significantly inhibited rolling and adhesion of endogenous leukocytes to the endothelium. A similar inhibition of leukocyte recruitment could be recorded after injection of Treg-derived tissue culture supernatant. Thus, these data indicate that soluble factors may account for the suppressive effects. Accordingly we found that IL-10, but not TGF-beta, was produced by Treg upon stimulation and that addition of anti-IL-10 antibodies abrogated the suppressive effects of Treg and tissue culture supernatant in CHS reactions. Moreover, CD4+ CD25+ T cells isolated from IL-10-/- mice were not able to suppress the immune response induced by hapten treatment in C57BL/6 mice. In conclusion, our data suggest that cytokine-dependent rather than cell-cell contact-dependent mechanisms play a pivotal role in the suppression of CHS reactions by Treg in vivo.     

In vivo expansion of CD4+Foxp3+ regulatory T cells mediated by GITR molecules

CD4(+)Foxp3(+) regulatory T cells (Treg cells) play an important role in maintaining self-tolerance as suppressive/regulatory CD4 T cells. In vitro analyses have revealed the characteristics of Treg cells, that is, hyporesponsiveness when stimulated via TCR in the presence of splenic APC. In this study, we report a new mAb, G3c, which can induce the expansion of Treg cells stimulated with anti-CD3 Ab along with splenic APC, the culture conditions in which Treg cells exhibit hyporesponsiveness. Surprisingly, G3c mAb recognized glucocorticoid-induced TNFR family-related proteins (GITR). G3c mAb had stronger co-stimulatory activity for both Treg cells and responder T cells than another anti-GITR Ab (DTA1) in vitro. The in vivo administration of G3c increased the number of Treg cells and had less effect in inducing anti-tumor immunity in normal mice, although G3c had some anti-tumor effect on non-Treg cells in the absence of Treg cells in vivo, in contrast to the anti-tumor therapeutic effect of DTA1 in normal mice. Therefore, we need to know that the manipulation of immune responses with the use of anti-GITR Abs results from a balance between co-stimulatory effects on Treg cells and on responder cells, and we must aim at a narrow window leading to the therapeutic effects.     

The maintenance of human CD4+ CD25+ regulatory T cell function: IL-2, IL-4, IL-7 and IL-15 preserve optimal suppressive potency in vitro

CD4+ CD25+ regulatory T cells (Tregs) have far-reaching immunotherapeutic applications, the realization of which will require a greater understanding of the factors influencing their function and phenotype during ex vivo manipulation. In murine models, IL-2 plays an important role in both the maintenance of a functional Treg population in vivo and the activation of suppression in vitro. We have found that IL-2 maintains optimal function of human CD4+ CD25+ Tregs in vitro and increases expression of both forkhead box protein 3, human nomenclature (FOXP3) and the distinctive markers CD25, cytotoxic T lymphocyte antigen-4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor superfamily member number 18 (GITR). Although IL-2 reduced spontaneous apoptosis of Tregs, this property alone could not account for the optimal maintenance of the regulatory phenotype. The inhibition of phosphatidylinositol 3-kinase (PI3K) signaling by LY294002, a chemical inhibitor of PI3K, abolished the maintenance of maximal suppressive potency by IL-2, yet had no effect on the up-regulation of FOXP3, CD25, CTLA-4 and GITR. Other common gamma chain (gammac) cytokines-IL-4, IL-7 and IL-15-had similar properties, although IL-4 showed a unique lack of effect on the expression of FOXP3 or Treg markers despite maintaining maximal regulatory function. Taken together, our data suggest a model in which the gammac cytokines IL-2, IL-4, IL-7 and IL-15 maintain the optimal regulatory function of human CD4+ CD25+ T cells in a PI3K-dependent manner, offering new insight into the effective manipulation of Tregs ex vivo.     

TGF-beta1 production by CD4+ CD25+ regulatory T cells is not essential for suppression of intestinal inflammation

Naturally occurring CD4+ CD25+ regulatory T cells (Treg) are potent suppressors of CD4+ and CD8+ T cell responses in vitro and inhibit several organ-specific autoimmune diseases. While most in vitro studies suggest that CD4+ CD25+ Treg cells adopt a cytokine-independent but cell contact-dependent mode of T cell regulation, their precise mechanism of suppression in vivo remains largely unknown. Here we examine the functional contribution of Treg cell-derived TGF-beta1 and effector T cell responsiveness to TGF-beta in CD4+ CD25+ T cell-mediated suppression of inflammatory bowel disease (IBD). We show that CD4+ CD25+ Treg cells from either TGF-beta1+/+ or neonatal TGF-beta1-/- mice can suppress the incidence and severity of IBD as well as colonic IFN-gamma mRNA expression induced by WT CD4+ CD25- effector T cells. Furthermore, TGF-beta-resistant Smad3-/- CD4+ CD25+ Treg cells are equivalent to WT Treg cells in their capacity to suppress disease induced by either WT or Smad3-/- CD4+ CD25- effector T cells. Finally, anti-TGF-beta treatment exacerbates the colitogenic potential of CD4+ CD25- effector T cells in the absence of CD4+ CD25+ Treg cells. Together, these data demonstrate that in certain situations CD4+ CD25+ T cells are able to suppress intestinal inflammation by a mechanism not requiring Treg cell-derived TGF-beta1 or effector T cell/Treg cell responsiveness to TGF-beta via Smad3.     

Increased interleukin-10 production by ASC-deficient CD4+ T cells impairs bystander T-cell proliferation

Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an important component of the inflammasome, functioning as an adaptor protein that facilitates the recruitment and activation of procaspases that in turn promote the maturation of interleukin-1β (IL-1β) and IL-18. Despite initial focus on the inflammatory properties of ASC there is emerging evidence that highlights the importance of ASC in facilitating adaptive immune responses. However, the cellular and molecular basis for the involvement of ASC in adaptive immunity remains largely unexplored. We have previously demonstrated that activated ASC-deficient T cells have dampened proliferative responses. We have therefore explored the underlying cellular mechanism(s) by which ASC regulates T-cell proliferation. We show that under activating conditions (anti-CD3/CD28 stimulation) in bulk T-cell cultures the presence of ASC(-/-) CD4(+) T cells is sufficient to suppress the proliferative responses of neighbouring T cells. Furthermore, ASC(-/-) CD4(+) T cells upon activation exhibit a suppressive cytokine profile, with elevated production of IL-10 and reduced secretion of T helper type 1 cytokines, interferon-γ and IL-2. This increase in IL-10 secretion within the activated ASC(-/-) CD4(+) T-cell compartment was not associated with a proportional increase in conventional Foxp3(+) regulatory T (Treg) cells. Interestingly, when equal numbers of fluorescence-activated cell sorted ASC(+/+) and ASC(-/-) Treg cells (CD4(+) CD44(intermediate/high) CD25(+)) were activated in vitro, the ASC(-/-) fraction produced significantly more IL-10 than their wild-type counterparts, suggesting that ASC(-/-) Treg cells have greater suppressive capacity. Collectively, these results imply that the ASC may influence the development and functioning of Treg cells.     

Beta2‐adrenergic receptor signaling in CD4+ Foxp3+ regulatory T cells enhances their suppressive function in a PKA‐dependent manner

Beta2‐adrenergic receptor (B2AR) signaling is known to impair Th1‐cell differentiation and function in a cAMP‐dependent way, leading to inhibition of cell proliferation and decreased production of IL‐2 and IFN‐γ. CD4⁺ Foxp3⁺ Treg cells play a key role in the regulation of immune responses and are essential for maintenance of self‐tolerance. Nevertheless, very little is known about adrenergic receptor expression in Treg cells or the influence of noradrenaline on their function. Here we show that Foxp3⁺ Treg cells express functional B2AR. B2AR activation in Treg cells leads to increased intracellular cAMP levels and to protein kinase A (PKA)‐dependent CREB phosphorylation. We also found that signaling via B2AR enhances the in vitro suppressive activity of Treg cells. B2AR‐mediated increase in Treg‐cell suppressive function was associated with decreased IL‐2 mRNA levels in responder CD4⁺ T cells and improved Treg‐cell‐induced conversion of CD4⁺ Foxp3^? cells into Foxp3⁺ induced Treg cells. Moreover, B2AR signaling increased CTLA‐4 expression in Treg cells in a PKA‐dependent way. Finally, we found that PKA inhibition totally prevented the B2AR‐mediated increase in Treg‐cell suppressive function. Our data suggest that sympathetic fibers are able to regulate Treg‐cell suppressive activity in a positive manner through B2AR signaling.     

Elevated effector cell sensitivity to Treg-cell suppression that is not associated with reduced Th17-cell expression distinguishes HIV+ asymptomatic subjects from progressors

Suppression mediated by Treg cells is a balance between Treg-cell suppressive potency versus sensitivity of effector cells to Treg-cell suppression. We assessed if this balance, along with Treg-cell number relative to the Treg-cell counter-regulatory cytokine IL-17, differs between asymptomatic HIV(+) subjects versus those who progress onto disease. Cross-over studies comparing Treg-cell potency, measured by effector cell proliferation or IFN-γ expression, from HIV-infected versus control subjects to suppress the proliferation of allogeneic control effector cells demonstrated increased sensitivity of CD4(+) CD25(-) effector cells from asymptomatic HIV(+) subjects to suppression, rather than an increase in the suppressive potential of their CD4(+) CD25(+) Treg cells. In contrast, HIV(+) progressors did not differ from controls in Treg-cell potency or effector cell sensitivity to Treg-cell suppression. Both CD4(+) CD25(+) Foxp3(+) Treg and effector IL-17 absolute cell numbers were significantly lower in all HIV(+) subjects tested and not restored by antiviral therapy. Thus, these novel data suggest that elevated Treg-cell-mediated suppression due to increased sensitivity of effectors to Treg cells may be a natural host response in chronic asymptomatic HIV infection, which is lost as disease progresses and that this feature of CD25(-) effector cells is not inextricably linked to reduced production of the Treg-cell counter-regulatory cytokine IL-17.     

Expansion of regulatory CD8+ CD25+ T cells after neonatal alloimmunization

Transplantation tolerance induced by neonatal injection of semi-allogeneic spleen cells is associated with a pathological syndrome caused by T helper type 2 (Th2) differentiation of donor-specific CD4(+) T lymphocytes. We have shown previously that this Th2-biased response is inhibited by host CD8(+) T cells. Herein, we demonstrate that upon neonatal immunization with (A/J × BALB/c)F(1) spleen cells, BALB/c mice expand a population of CD8(+) T cells expressing both CD25 and forkhead box P3 (FoxP3) markers. In this setting, CD8(+) CD25(+) T cells predominantly produce interferon (IFN)-γ and interleukin (IL)-10 and are efficient in controlling IL-4, IL-5 and IL-13 production by donor-specific CD4(+) T cells in vitro. CD8(+) FoxP3(-) T cells are single producers of IFN-γ or IL-10, whereas CD8(+) FoxP3(+) T cells are double producers of IFN-γ and IL-10. We further demonstrate that IFN-γ and IL-10 are two major cytokines produced by CD8(+) T cells involved in the in vivo regulation of Th2-type pathology. In this setting, we conclude that neonatal alloimmunization induces the expansion of several regulatory CD8(+) T cells which may control Th2 activities via IFN-γ and IL-10.     

Development and function of naturally occurring CD4+CD25+ regulatory T cells

The immune system has evolved numerous mechanisms of peripheral T cell immunoregulation, including a network of regulatory T (Treg) cells, to modulate and down-regulate immune responses at various times and locations and in various inflammatory circumstances. Amongst these, naturally occurring CD4(+)CD25(+) Treg cells (nTreg) represent a major lymphocyte population engaged in the dominant control of self-reactive T responses and maintaining tolerance in several models of autoimmunity. CD4(+)CD25(+) Treg cells differentiate in the normal thymus as a functionally distinct subpopulation of T cells bearing a broad T cell receptor repertoire, endowing these cells with the capacity to recognize a wide range of self and nonself antigen specificities. The generation of CD4(+)CD25(+) Treg cells in the immune system is genetically controlled, influenced by antigen recognition, and various signals, in particular, cytokines such as interleukin-2 and transforming growth factor-beta1, control their activation, expansion, and suppressive effector activity. Functional abrogation of these cells in vivo or genetic defects that affect their development or function unequivocally promote the development of autoimmune and other inflammatory diseases in animals and humans. Recent progress has shed light on our understanding of the cellular and molecular basis of CD4(+)CD25(+) Treg cell-mediated immune regulation. This article discusses the relative contribution of CD4(+)CD25(+) nTreg cells in the induction of immunologic self-tolerance and provides a comprehensive overview of recent finding regarding the functional properties and effector mechanism of these cells, as revealed from various in vitro and in vivo models.     

树突状细胞扩增抗原特异性CD4+ CD25+调节性T细胞研究进展

CD4+CD25+调节性T细胞(Tr)是同时具有免疫低反应性和免疫抑制性功能两大特征的T细胞.研究证实,CD4+ CD25+ Tr在抑制器官特异性自身免疫性疾病及GVHD是抗原特异性的,因此,应用器官特异性而不是多克隆性的Tr将大大促进以Tr为基础的免疫治疗.而具有调节活性的CD4+ CD25+ Tr仅占人类外周血CIM+ T细胞的1%～2%,因此,研究体外大量扩增的方法 对于以Tr基础的治疗至关重要.研究表明,树突状细胞(DC)作为机体强有力的专职抗原递呈细胞可以扩增具有抗原特异性的CD4+ CD25+ Tr且能增加后者的抑制活性,这为治疗自身免疫性疾病及GVHD提供了新的治疗前景.