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At least 127 records · Page 7Linked to original sources
PubMed2004

Interleukin-2 is essential for CD4+CD25+ regulatory T cell function.

Constitutive expression of CD25, the IL-2 receptor alpha-chain, defines a distinct population of CD4+ T cells (Treg) with suppressive activity in vitro and in vivo. IL-2 has been implicated in the generation and maintenance of Treg, however, a functional contribution of the IL-2 receptor during suppression is thus far unknown. We show that IL-2 is required for Treg function in vitro, since suppression is completely abrogated by selective blocking of the IL-2 receptor on Treg during co-culture with responder T cells. We demonstrate that Treg, which do not produce IL-2, compete for IL-2 secreted by responder T cells. In accordance with the idea of competition being part of the suppressive mechanism, in vitro neutralization of IL-2 mimics all effects of Treg. Conversely, recombinant IL-2 abrogates inhibition of IL-2 production in responder T cells, the hallmark of Treg suppression. Finally, activation in the presence of IL-2 primes Treg to produce IL-10 upon secondary stimulation, indicating that IL-2 uptake is also required to induce additional suppressive factors that might be more relevant for suppression in vivo. We propose the parakrine uptake of soluble mediators as a flexible mechanism to adapt Treg activity to the strength of the responder T cell reaction.

Animals↗
PubMed2006

The blind-spot of regulatory T cells.

CD4+ CD25+ Foxp3+ regulatory T cells (Treg) are natural suppressors of autoimmunity but they can also dampen the effective clearance of infectious organisms. These cells have the potential to be exploited to prevent transplant rejection and to treat autoimmune disease. A paper in this issue of the European Journal of Immunology details a method to selectively expand antigen-specific Treg from a polyclonal Treg population, by using a specific dendritic cell (DC) subset. Furthermore, the authors show that such Treg can be used to prevent experimental type I diabetes; however, as Treg are positively selected by thymic epithelial cells (TEC) on the basis of self-reactivity, they would systematically suppress protective immune responses unless their repertoire is devoid of recognition towards peripheral antigen-presenting cells. This may be achieved by negative selection of developing Treg on thymic DC, thus creating a 'blind-spot' corresponding to DC-self-antigens in the mature Treg repertoire. Therefore, therapeutic use of DC subsets for the expansion of rare Treg populations should take into account this blind-spot, as peptides that are not accessible to thymic DC may be significantly more effective for the expansion of Treg.

Animals↗
PubMed2003

High antigen dose and activated dendritic cells enable Th cells to escape regulatory T cell-mediated suppression in vitro.

CD4+CD25+ regulatory T cells (Tregs) are critical for peripheral tolerance and prevention of autoimmunity. In vitro coculture studies have revealed that increased costimulation breaks Treg-mediated suppression in response to anti-CD3 or antigen. However, it was unclear whether loss of suppression arose from inactivation of Tregs or whether increased stimulation caused Th cells to escape suppression. We have investigated conditions that allow or override Treg-mediated suppression using DO11.10 TCR-transgenic T cells and chicken ovalbumin peptide 323-339-pulsed antigen-presenting cells. Treg suppression of Th proliferation is broken with potent stimulation, using activated spleen cells and high antigen dose, but is intact at low antigen dose. Costimulation with CD80 and CD86 expressed on activated dendritic cells was essential for Th cell escape from suppression at a high antigen dose. Potently stimulated Tregs were functional since they reduced levels of IL-2, IFN-gamma, IL-4 and Th CD25 expression in cocultures. Furthermore, Tregs responding to high antigen dose and activated splenocytes retained the ability to suppress proliferation, but only of Th cells responding to a sub-optimal dose of independent antigen. Together, our results demonstrate that under conditions of strong antigen-specific stimulation, Tregs remain functional, but Th cells escape Treg-mediated suppression.

Animals↗
PubMed2006

Function and recruitment of mucosal regulatory T cells in human chronic Helicobacter pylori infection and gastric adenocarcinoma.

CD4(+)CD25(high) FOXP3-expressing regulatory T cells (Treg) can suppress immune responses to infections and tumors, thereby promoting microbial persistence and tumor progression. However, little is known about the phenotype and function of human mucosal Treg. Therefore, we analyzed the suppressive activity and homing phenotype of Treg in gastric mucosa of Helicobacter pylori-infected gastric adenocarcinoma patients. We found increased numbers of CD4(+)FOXP3(+) Treg in the tumor compared to tumor-free gastric mucosa. Gastric Treg cells were able to suppress H. pylori-induced T cell proliferation and IFN-gamma production. Furthermore, gastric Treg expressed increased levels of l-selectin and CCR4, compared to non-Treg cells, suggesting that these receptors contribute to Treg recruitment. The presence of functional antigen-specific Treg in H. pylori-infected gastric mucosa supports an important role for these cells in suppression of mucosal effector T cell responses, which probably contribute to bacterial persistence and possibly also to gastric tumor progression.

Adenocarcinoma↗
PubMed2006

Imaging the function of regulatory T cells in vivo.

Despite extensive research on regulatory T cells (Tregs) since their rebirth more than twenty years ago, the cellular and molecular mechanisms by which they act to suppress immune responses remain largely elusive. In vitro suppression assays are instrumental in the functional identification of these cells. However, suppressive mechanisms defined in in vitro assays might not be relevant to situations in vivo. Advances in live tissue and intravital imaging technologies combined with the ability to grow large numbers of Tregs for in vivo experimentation have created an opportunity to analyze Treg function in vivo in their native environment in real-time. Two-photon laser-scanning microscopic studies of Treg control of lymph node priming suggest that Tregs exert their function by limiting T helper (Th) cell access to dendritic cells (DCs). In the absence of Tregs, Th cells initially form transient interactions with DCs that lead to arrest of the Th cells and to the formation of stable conjugates between Th cells and DCs. In the presence of increasing number of Tregs, Th cell arrest and their prolonged contacts with DCs are progressively inhibited. The reduced DC contacts in the presence of Tregs are associated with suppressed proliferation and differentiation of Th cells. Expansion of such analysis to peripheral tissues together with the development of functional reporter mice will help to further elucidate the mode of operation of Tregs in vivo.

Animals↗
PubMed2006

Antigen-specific regulatory T-cell subsets in transplantation tolerance regulatory T-cell subset quality reduces the need for quantity.

Regulatory T cells (Treg) are critical controllers of the immune response. Disturbed Treg function results in autoimmunity, whereas in transplantation Treg are crucial in graft survival and transplant tolerance. Hence therapeutic modalities that influence Treg numbers or function hold great clinical opportunity. Ahead of us are clinical trails studying in vivo Treg induction protocols and immunotherapy with ex vivo expanded Treg. Here we discuss the preferential use and/or induction of antigen-specific Treg subsets with high suppressive power and migratory capacity as a potential therapeutic tool to prevent solid organ transplantation rejection. Accordingly, ex vivoselection procedures to induce and isolate highly suppressive antigen-specific Treg (subsets) are needed. This subject, as well as the Treg-facilitating potential of immunosuppressive agents, is discussed.

Animals↗
PubMed2005

Effects of interleukin 4 on CD25+CD4+ regulatory T cell function.

CD25+CD4+ regulatory T cells (Tregs) contribute to the maintenance of peripheral tolerance against self and non-self. The modulatory effects of cytokines, such as interleukin 4 (IL-4) on the function of Tregs have not been explored in detail. We here report that IL-4 prevents spontaneous apoptosis and the decline of foxp3 mRNA which were found to occur during culture of isolated Tregs. Tregs exposed to IL-4 were more potent in suppressing the proliferation of naïve CD4+ T cells and they better inhibited IFN-gamma production by CD4+ T cells as compared to Tregs cultured in medium. IL-4 also enhanced membrane IL-2Ralpha (CD25) expression on Tregs above the levels observed on freshly isolated cells. IL-4-mediated effects on Treg function persisted in Tregs from Stat6-/- mice, pointing to a Stat6-independent intracellular transduction pathway. In conclusion, our data suggest that the anti-inflammatory function of IL-4 could partly be mediated by effects on Tregs function.

Animals↗
PubMed2006

Regulatory T cells and Toll-like receptors in tumor immunity.

Regulatory T (Treg) cells induce immune tolerance by suppressing host immune responses against self- or non-self-antigens, thus playing critical roles in preventing autoimmune diseases. However, tumor cells may take advantage of Treg cells to protect themselves from immune attack elicited by vaccines. Recent studies demonstrate the presence of Treg cells in various types of cancers and their suppressive function. Therefore, Treg cells at tumor sites have detrimental effects on immunotherapy directed to cancer and infectious diseases. This review will discuss antigen specificity of Treg cells, the factors that contribute to Treg cell generation and suppressive function, and their regulation through Toll-like receptor signaling. It was generally though that TLR-mediated recognition of specific structures of invading pathogens initiate innate as well as adaptive immune responses through dendritic cells. New evidence suggests that TLR signaling may directly regulate the suppressive function of Treg cells. Linking TLR signaling to the functional control of Treg cells opens intriguing opportunities to shift the balance between CD4(+) T-helper and Treg cells, in ways that may improve the outcome of cancer immunotherapy.

Animals↗
PubMed2006

Use of FoxP3 expression to identify regulatory T cells in healthy dogs and dogs with cancer.

Regulatory T cells (Treg) are a distinct group of T lymphocytes with immunosuppressive properties that serve normally to prevent harmful autoimmune responses. However, Tregs can also interfere with beneficial immune responses such as anti-tumor and anti-viral immunity in humans and rodents. Given the overall importance of Tregs, it is likely that they play an important role in diseases of dogs as well. However, at present reagents required for identification of Tregs in dogs are not available. Therefore, we investigated whether expression of FoxP3, a transcription factor that is highly expressed in Tregs in humans and rodents could also be used to identify Tregs in dogs. We found that a cross-reactive FoxP3 antibody identified a subset of CD4(+) T cells in blood and lymph nodes of dogs. By flow cytometry the mean percentage of FoxP3(+)CD4(+) T cells in normal dogs was 4.3% in blood and 9.8% in the lymph nodes. In dogs with cancer, there was a significant increase in numbers of Treg in blood (7.5%) and tumor-draining lymph nodes (17.1%) compared to age-matched healthy control dogs. We also found that FoxP3(+)CD4(+) T cells in dogs could be significantly expanded in vitro by TCR activation together with addition of TGF-beta and IL-2. Treated cells also significantly increased expression of TGF-beta and IL-10mRNA. We conclude from these studies that a cross-reactive FoxP3 antibody can be used to identify Tregs in dogs and that this reagent may serve as a useful tool for investigating the role of Treg in a variety of diseases of dogs.

Animals↗
PubMed2006

Regulating regulatory T cells.

Regulatory T cells (Tregs) are a specialized subpopulation of T cells that act to suppress activation of other immune cells and thereby maintain immune system homeostasis, self-tolerance as well as control excessive response to foreign antigens. The mere concept of Tregs was the subject of significant controversy among immunologists for many years owing to the paucity of reliable markers for defining these cells and the ambiguity of the nature and molecular basis of suppressive phenomena. However, recent advances in the molecular characterization of this cell population have firmly established their existence and their vital role in the vertebrate immune system. Of interest, accumulating evidence from both humans and experimental animal models has implicated the involvement of Tregs in the development of graft-versus-host disease (GVHD). The demonstration that Tregs could separate GVHD from graft-versus-tumor (GVT) activity suggests that their immunosuppressive potential could be manipulated to reduce GVHD without detrimental consequence on GVT effect. Although a variety of T lymphocytes with suppressive capabilities have been reported, the two best-characterized subsets are the naturally arising, intrathymic-generated Tregs (natural Tregs) and the peripherally generated, inducible Tregs (inducible Tregs). This review summarizes our current knowledge of the generation, function and regulation of these two populations of Tregs during an immune response. Their role in the development of GVHD and their therapeutic potential for the prevention and treatment of GVHD will also be described.

Animals↗
PubMed2007

Defining target antigens for CD25+ FOXP3 + IFN-gamma- regulatory T cells in chronic hepatitis C virus infection.

The mechanism behind the apparent lack of effective antiviral immune responses in chronic hepatitis C virus (HCV) patients is poorly understood. It remains unclear if natural regulatory T cells (Treg) contribute to the induction and maintenance of HCV persistence. We herein report for the first time that CD25(high)IFN-gamma(-)FOXP3(high) Tregs can be rapidly induced by culturing peripheral blood mononuclear cells (PBMCs) of HCV-positive patients with HCV protein-derived peptides. The HCV-specific Tregs, generally CD4(+)CD45RO(+), did not proliferate in response to HCV peptide and failed to produce interferon (IFN)-gamma, in distinct contrast to antiviral effector cells. Stimulation of healthy donor PBMCs with HCV peptides did not result in CD25 and FOXP3 upregulation above non-antigen background. To further investigate the antigen specificity of these potentially disease-associated natural Tregs, CD25(+) cells were isolated from PBMCs, labeled with carboxyfluorescein diacetate succinimidylester and added back to CD25-depleted PBMCs, and the co-cultures were then stimulated with individual peptides derived from the HCV core protein. We found that the actual peptide that can stimulate Treg varied between patients, but within any given subject only a small number of the peptides were able to stimulate Treg, suggesting the existence of dominant Treg epitopes. Although functional experiments for these peptides are ongoing in our laboratory, data presented here suggests that HCV-specific natural Tregs are abundant in infected individuals, in contrast to the extremely low frequency of anti-HCV effector T cells, supporting the view that natural Treg may be implicated in host immune tolerance during HCV infection.

Epitopes, T-Lymphocyte↗
PubMed2003

Lymphocyte populations in human lymph nodes. Alterations in CD4+ CD25+ T regulatory cell phenotype and T-cell receptor Vbeta repertoire.

Here we provide a description of lymphocyte populations in human lymph nodes (LN) with a special emphasis on the CD4+ lymphocyte population constitutively expressing CD25 at a high level and endowed with immunoregulatory properties [T regulatory (Treg) cells]. Lymph nodes were analysed by multicolour flow cytometry in parallel with correspondent peripheral blood (PB). Immunomagnetically purified Treg cells were tested for anergy and suppressive activity in a CD3/T-cell receptor (TCR)-driven proliferation assay. Compared to PB, there was a reduced T/B lymphocyte ratio in LN. Both LN and PB contained a similar proportion of CD4+ lymphocytes but, conversely, CD8+ lymphocytes were less represented in PB, with a consequent increase in the ratio of CD4+/CD8+ natural killer cells were <2% (PB range 6-22%). No significant differences existed in the frequency of the other lymphocyte subpopulations examined (naïve-type CD4+ and CD8+ lymphocytes, activated B and CD4+ lymphocytes, and effector-type CD8+ lymphocytes). LN and PB contained similar percentages of CD4+ lymphocytes constitutively expressing intermediate or high levels of CD25. CD4+ CD25++ cells constitutively coexpressed high levels of CD152 and were therefore identified as Treg cells. Treg cells in LN and PB differed in terms of CD45RB, HLA-DR, CD45RO, and CD62L expression. Also the TCRVbeta repertoire diverged between Treg cells from LN and PB. Similar to Treg cells from PB, Treg cells from LN were anergic and efficiently inhibited other CD4+ and CD8+ lymphocyte proliferation. This study extends the information on the diversities in lymphocyte composition between human LN and PB, and reports for the first time a description of the phenotypic and functional characteristics of Treg cells in human LN, highlighting the importance of the LN microenvironment in shaping the surface phenotype of Treg cells.

Adult↗
PubMed2006

Effective expansion of alloantigen-specific Foxp3+ CD25+ CD4+ regulatory T cells by dendritic cells during the mixed leukocyte reaction.

Thymic-derived CD25+ CD4+ T regulatory cells (Tregs) suppress immune responses, including transplantation. Here we evaluated the ability of dendritic cells (DCs) to expand alloantigen-specific Tregs in the mixed leukocyte reaction (MLR) that develops from polyclonal populations of T cells. The allogeneic DCs, when supplemented with IL-2 in the cultures, were much more effective than bulk spleen cells in expanding the numbers of Tregs. Likewise, DCs and not spleen cells were effective in sustaining expression of the transcription factor Foxp3 in Tregs, but neither IL-2 nor CD80/86 was required for this effect in the cultures. On a per-cell basis, the DC-expanded, but not unexpanded, Tregs were more potent suppressors of a fresh MLR by CD25- CD4+ T cells. Suppression was 3- to 10-fold more active for MLRs induced by the original alloantigens than for third-party stimulators. When DC-expanded Tregs were introduced into sublethally irradiated hosts, the T cells suppressed graft-versus-host-disease induced by CD25- CD4+ T cells. Again, suppression was more active against the same mouse strain that provided the DCs to expand the Tregs. Therefore, alloantigen-selected Tregs are more effective suppressors of responses to major transplantation antigens, and these Tregs can be expanded from a polyclonal repertoire by DCs.

Animals↗
PubMed2006

Heme oxygenase-1 is not required for mouse regulatory T cell development and function.

CD4 regulatory T cells (Treg) ensure peripheral tolerance to self-antigens and limit the deleterious effects associated with inflammatory and immune responses by mechanisms that remain to be fully understood. The enzyme heme oxygenase-1 (HO-1), through its known anti-inflammatory activity, is a candidate for a functional role in Treg activity. We compared wild-type and heme oxygenase-1-deficient (hmox-1(-/-)) mice in order to assess the role of HO-1 in mouse Treg development and function under physiologic conditions. The frequency of CD25+ and Foxp3+ Treg was similar in hmox-1(-/-) and hmox-1(+/+) mice. More importantly, CD4+ CD25+ Treg purified from either hmox-1(-/-) or hmox-1(+/+) mice were equally efficient in controlling the proliferation in vitro and the expansion in vivo of CD4+ CD25- T cells, whether or not these responder cells expressed HO-1. In addition, induction of expression of HO-1 in vivo did not affect Treg suppressor function. As shown before, expression of HO-1 was higher in Treg than in naive T cells; however, naturally activated Foxp3- T cells displayed equal amount of HO-1 mRNA as Treg. Finally, we conclude that under physiological conditions in mice, Treg development, maintenance and function are independent of HO-1 activity.

Animals↗
PubMed2006

Regulatory T cells and systemic lupus erythematosus.

CD4+CD25+ regulatory T cells (Treg) constitute an important mechanism of peripheral immune tolerance. Organ-specific autoimmune conditions, such as thyroiditis and insulin-dependent diabetes mellitus have been attributed to a breakdown of this tolerance mechanism. However, this T-cell subset has not been well studied in patients and mice with systemic lupus erythematosus (SLE; lupus). The information that has been gathered so far using new tools that discriminate Treg from activated T cells indicates that reduced numbers of Treg may exist in patients with lupus. In addition, potential defects in SLE Treg function have been documented in humans and mice. Our group has demonstrated equivalent proportions of thymic Treg in lupus prone and normal mice. We therefore propose that Treg function in SLE is the more important factor to address in future studies of murine lupus. Recent studies have shown that Toll-like receptor (TLR) ligation can result in an abrogation of Treg-mediated suppression; specifically ligation of TLR-2, -4, -8 and -9. We address this new information about TLRs and Treg and propose a model for Treg tolerance breakdown to nucleic acid-binding SLE autoantigens.

Animals↗
PubMed2005

Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer.

Cyclooxygenase (COX)-2 and its product prostaglandin (PG) E2 underlie an immunosuppressive network that is important in the pathogenesis of non-small cell lung cancer. CD4+ CD25+ T regulatory (Treg) cells play an important role in maintenance of immunologic self-tolerance. CD4+ CD25+ Treg cell activities increase in lung cancer and appear to play a role in suppressing antitumor immune responses. Definition of the pathways controlling Treg cell activities will enhance our understanding of limitation of the host antitumor immune responses. Tumor-derived COX-2/PGE2 induced expression of the Treg cell-specific transcription factor, Foxp3, and increased Treg cell activity. Assessment of E-prostanoid (EP) receptor requirements revealed that PGE2-mediated induction of Treg cell Foxp3 gene expression was significantly reduced in the absence of the EP4 receptor and ablated in the absence of the EP2 receptor expression. In vivo, COX-2 inhibition reduced Treg cell frequency and activity, attenuated Foxp3 expression in tumor-infiltrating lymphocytes, and decreased tumor burden. Transfer of Treg cells or administration of PGE2 to mice receiving COX-2 inhibitors reversed these effects. We conclude that inhibition of COX-2/PGE2 suppresses Treg cell activity and enhances antitumor responses.

Animals↗
PubMed2004

Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD.

CD4+CD25+ regulatory T (Treg) cells are potent modulators of alloimmune responses. In murine models of allogeneic bone marrow transplantation, adoptive transfer of donor CD4+CD25+ Treg cells protects recipient mice from lethal acute graft-versus-host disease (aGVHD) induced by donor CD4+CD25- T cells. Here we examined the differential effect of CD62L+ and CD62L- subsets of CD4+CD25+ Treg cells on aGVHD-related mortality. Both subpopulations showed the characteristic features of CD4+CD25+ Treg cells in vitro and did not induce aGVHD in vivo. However, in cotransfer with donor CD4+CD25- T cells, only the CD62L+ subset of CD4+CD25+ Treg cells prevented severe tissue damage to the colon and protected recipients from lethal aGVHD. Early after transplantation, a higher number of donor-type Treg cells accumulated in host mesenteric lymph node (LN) and spleen when CD4+CD25+CD62L+ Treg cells were transferred compared with the CD62L- subset. Subsequently, CD4+CD25+CD62L+ Treg cells showed a significantly higher capacity than their CD62L- counterpart to inhibit the expansion of donor CD4+CD25- T cells. The ability of Treg cells to efficiently enter the priming sites of pathogenic allo-reactive T cells appears to be a prerequisite for their protective function in aGVHD.

Acute Disease↗
PubMed2006

Human CD4+CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop.

CD4+CD25+ regulatory T lymphocytes (Tregs) are specialized T cells playing a key role in the control of immune homeostasis. Here, we show that human Tregs constitutively express tyrosine hydroxylase (TH, EC 1.14.16.2), the rate-limiting enzyme in the synthesis of catecholamines, and contain substantial amounts of dopamine, norepinephrine, and epinephrine, which are released upon treatment with reserpine. Catecholamine release results in reduced production of interleukin-10 and transforming growth factor-beta by Tregs, and in down-regulation of Treg-dependent inhibition of effector T-lymphocyte (Teff) proliferation, which occurs without affecting the production of tumor necrosis factor-alpha or interferon-gamma. Tregs and Teffs express on the cell membrane both D1-like and D2-like dopaminergic receptors to a similar extent (12%-29% of the cells). Catecholamine-dependent down-regulation of Tregs is, however, selectively reversed by pharmacological blockade of dopaminergic D1-like receptors, which in Tregs only (and not in Teffs) are also expressed at the level of mRNA and are functionally coupled to intracellular production of cAMP. These findings indicate that in human Tregs endogenous catecholamines subserve an autocrine/paracrine loop involving dopaminergic pathways and resulting in down-regulation of Treg function.

Autocrine Communication↗