Role Of Treg Cells Research Articles

The Role of Treg Cells in the Cancer Immunological Response

Problem statement: T cell-mediated immunosuppression has been observed for decades without clarification as to which factor was responsible for this observation. The identification of CD4+CD25+ regulatory T (Treg) cells represents a milestone in the filed of immunology and provides an explanation for T-cell-mediated immunosuppression. Although Treg cells were originally identified for their ability to prevent organ-specific autoimmune disease in mice, emerging evidence suggests that Treg cells play a pivotal role in tumor immunity and contribute to tumor growth and progression, thereby having an important impact on the outcome of cancer patients. Approach: This article reviewed the medical literature to describe how Treg cells affect anti-tumor immunity. Results: Treg cells suppressed anti-tumor immunity by inhibiting the effector functions of tumor-specific T cells and NK cells. Importantly, tumor cells played an active role in recruiting and generating Treg cells and creating a suppressive tumor microenvironment. Strategies to deplete Treg cells or inhibit their function had yielded promising results by enhancing anti-tumor immunity in experimental studies as well as clinical practice. Conclusion: A better understanding of the pathophysiology of Treg cells not only increased our knowledge in a variety of aspects of immunology but also potentially benefited cancer patients.

Regulatory T cells (Treg) in rheumatoid arthritis

Modulation of the T-cell response depends chiefly on regulatory T cells (Treg), which express CD4 and CD25. Some Treg cells are present naturally, whereas others are induced in response to antigens. The immunomodulating effects of Treg cells are mediated by membrane molecules (e.g., CTLA4, GITR, and OX40) and cytokines. IL-35 seems to be a crucial mediator, although IL-10 and TGFβ are also important. The role for Treg cells in rheumatoid arthritis (RA) has been established in both patients and animal models. Treg function is deficient in RA, whereas Treg counts vary. Treg counts increase in patients who are responding to TNFα antagonist therapy. Among current hypotheses, Treg expansion or transfer may hold promise for the treatment of RA.

Effect of post-neonatal thymectomy on body weight gain in Swiss mice: The role of regulatory T-cells and the hypothalamic arcuate nucleus

Effect of post-neonatal thymectomy on body weight gain in Swiss mice: The role of regulatory T-cells and the hypothalamic arcuate nucleus

Inhibitor Development

The immune response to factor VIII and the development of inhibitory antibodies is a complex multi-factorial process involving a variety of immune regulatory genes and cells, several of which have the potential to determine risk. A better understanding of the mechanisms involved will increase the likelihood of development of new therapeutic options for patients with hemophilia. This review summarizes genetic and non-genetic risk factors currently under evaluation, and the potential modulative effect of the von Willebrand factor on factor VIII immuno- and antigenicity. In addition, the role of T-regulatory cells in the pathogenicity of inhibitors will be discussed.

Relationship between Treg Cell and cancer immunity

Many studies demonstrate the existence of regulatory T(Treg)cell at tumot sites,implying that these Treg cells may induce local immune tolerance.Deep studies on the role of Treg cells in cancer patients will offer new approaches for tumor immunotherapy. Key words: T-lymphocytes; Neoplasms; Immunotherapy

Regulatory T cells alleviate allergic airway hyper‐responsiveness by modulating angiogenesis of airway remodelling via Notch signaling pathway

Chronic inflammation and airway remodelling are two key features of asthma. Whilst CD4+CD25+ Treg cells have been shown to prevent allergen induced airway inflammation, the role of Treg cells in asthma with established airway remodelling has not been investigated. To address this issue, we induced airway remodelling in OVA‐sensitized mice by chronic aerosol OVA exposure, followed by adoptive transfers of OVA peptide‐specific Treg cells. Without further allergen challenges, residual leukocyte infiltrates in the lungs can be found regardless of the cell types transferred. Airway hyper‐responsiveness (AHR) and pulmonary vasculature were significantly reduced after Treg transfers (P<0.001), suggesting a relationship between pulmonary vasculature and AHR and an anti‐angiogenic effect of Treg cells in airway remodelling. A direct anti‐angiogenic function of Treg cells was validated by both in vitro and in vivo angiogenesis assays which showed a significant reduction of vessel formation at the presence of Treg cells (P<0.001). Notch signaling pathway is known to regulate both peripheral T cell differentiation and angiogenesis. We found that the anti‐angiogenic effect of Treg cells was abrogated by pre‐incubation with recombinant Notch‐Fc proteins. This study demonstrates a novel function of Treg cells in chronic airway inflammation where Treg inhibits angiogenic remodelling via Notch signaling pathway.The project was supported by grants from the Taiwan National Science Council and National Taiwan University Hospital.

Expression of CD4+ CD25+ CD127(low/-) T cells in patients with systemic lupus erythematosus

To detect the new and old surface markers of regulatory T cells (Treg cells) in the CD4+ T cells of the patients with systemic lupus erythematosus (SLE) in order to reveal the role of Treg cells in the pathogenesis of SLE. Peripheral blood samples were collected from 29 newly diagnosed and treatment-naïve SLE patients, 3 males and 26 females, aged (34 +/- 13), and 24 sex and aged-matched healthy controls. Three-color flow cytometry was used to detect the CD4+CD25+ CD127(low/-) T cells, CD4+CD25high T cells, and CD4+CD25+FOXP3+ T cells. The serum anti-nuclear antibody (ANA), anti-ds-DNA antibody, anti-smooth muscle antibody, anti-nucleosome antibody, anti-C1q, C3, and C4 were detected. Blood and urine routine examinations were conducted. The proportion of blood CD4+ CD25+CD127(low/-) T cells of the SLE patients was not significantly different from that of the controls (P > 0.05), however, the proportions of CD4+CD25+FOXP3+ T cells and CD4+CD25high T cells of the SLE patients were 2.1 +/- 1.2 and 0.8 +/- 0.4 respectively, both significantly lower than those of the controls (4.0 +/- 1.4 and 1.8 +/- 0.8 respectively, both P <0.01). The ratios of the CD4+CD25+CD127(low/-) T cells, CD4+CD25high T cells, and CD4+CD25+FOXP3+ T cells to the CD4+CD25+ T cells of the SLE patients were 0.5 +/- 0.1, 0.1 +/- 0, and 0.3 +/- 0.1 respectively, all significantly lower than those of the controls (0.6 +/- 0.1, 0.2 +/- 0.1, and 0.5 +/- 0. respectively, all P <0.01). The level of CD4+CD25+CD127(low/-) T cell was positively correlated with the levels of CD4+CD25+FOXP3+ T cells and CD4+CD25high T cell (both P < 0.01). The levels of these 3 kinds of cells and their ratios to CD4+CD25+ T cells had no correlation with age, sex, course, IgG, IgA, IgM, urine protein, TIPU, anti-dsDNA, anti-C1q, anti-nuclear body antibody (all P > 0.05), however, were significantly associated negatively with SLE disease activity index, P < 0.05). Only the CD4+CD25+CD127(low/-) T cells/ CD4+CD25+ T cells was negatively correlated with C4 (P <0.01). The relative ratio of Treg cells to the activated CD4+ T cells may play an important role in the pathogenesis of SLE.

373: What is the Role for Regulatory T-cells after Nonmyeloablative Conditioning?

373: What is the Role for Regulatory T-cells after Nonmyeloablative Conditioning?

The role of T-regulatory cells in pregnancy and cancer

The acceptance of paternally-derived alloantigens during pregnancy and escape from host immunosurveillance by cancer are based on similar immunological mechanisms. Among them both natural and peripherally-induced T CD4+ CD25+ Foxp3+ and Tr1 regulatory cells (Tregs) play important role. Interactions of Tregs with other immunocytes including dendritic cells, mechanisms of Tregs recruitment and their suppressive properties in cancer and pregnancy have been presented in this paper. Despite the fact that mechanisms of Treg regulation are still in progress, there is a hope for use of Tregs-related immunotherapy in clinical practice, and the first attempts of such management have already been described. However, more information about the function of Tregs cells is needed to provide safe treatment devoid of potential side-effects. Resolving the secrets of Tregs cells will probably offer new options of cancer treatment and will help to improve the management of pregnancy failure.

CD4+CD25+ Regulatory T Cells in Patients with Acute Lymphocytic Leukemia.

Human CD4+CD25+ regulatory T (Treg) cells suppress antigen-specific T cell immune response and contribute to peripheral tolerance. However, little is known about the role of Treg cells in the pathogenesis of acute lymphocytic leukemia (ALL). In this study, the proportion of CD4+CD25+ Treg cells in the peripheral blood of three groups of people [the patients with ALL who had never received any chemotherapy before, the patients with ALL who had achieved partial remission (PR) or complete remission (CR) after chemotherapy and the healthy donors] was evaluated by flow cytometry. The expression level of Foxp3 mRNA of each group was examined by real-time RT-PCR. In vitro, the peripheral blood mononuclear cells (PBMC) from healthy donors were cultured in the serum of ALL patients without chemotherapy; each group was divided into sub-groups according to various serum doses. After co-cultured for 72 hours, the cells of all the groups were harvested separately and further tested the number of CD4+CD25+ Treg cells and the mRNA expression of Foxp3. The results showed that both the percentage of CD4+CD25+ T cells and the mRNA expression level of Foxp3 in patients with chemotherapy were significantly higher than those of the healthy donors and patients without chemotherapy (P<0.01 and P<0.01). Although the population of CD4+CD25+ T cells in ALL patients without chemotherapy was almost the same to that in the healthy donors (P>0.05), the expression of Foxp3 mRNA in former was higher (P<0.05) .The serum derived from ALL patients without chemotherapy remarkably increased the proportion of CD4+CD25+ T cells and the expression level of Foxp3 mRNA in co-cultured system, both of which were statistically higher than those in controls (P<0.05 and P<0.01) and did not vary with the serum dose. These results suggest that the chemotherapy may exert an influence on the production of CD4+CD25+ Treg cells and CD4+CD25+ Treg cells may play an important role in the pathogenesis of ALL.

Despite Increased CD4+Foxp3+ Cells within the Infection Site, BALB/c IL-4 Receptor-Deficient Mice Reveal CD4+Foxp3-Negative T Cells as a Source of IL-10 inLeishmania majorSusceptibility

BALB/c IL-4Ralpha(-/-) mice, despite the absence of IL-4/IL-13 signaling and potent Th2 responses, remain highly susceptible to Leishmania major substain LV39 due exclusively to residual levels of IL-10. To address the contribution of CD4(+)CD25(+) T regulatory (Treg) cells to IL-10-mediated susceptibility, we depleted CD4(+)CD25(+) cells in vivo and reconstituted IL-4Ralpha x RAG2 recipients with purified CD4(+)CD25(-) T cells. Although anti-CD25 mAb treatment significantly decreased parasite numbers in IL-4Ralpha(-/-) mice, treatment with anti-IL-10R mAb virtually eliminated L. major parasites in both footpad and dermal infection sites. In addition, IL-4Ralpha x RAG2 mice reconstituted with CD4(+) cells depleted of CD25(+) Treg cells remained highly susceptible to infection. Analysis of L. major-infected BALB/c and IL-4Ralpha(-/-) inflammatory sites revealed that the majority of IL-10 was secreted by the CD4(+)Foxp3(-) population, with a fraction of IL-10 coming from CD4(+)Foxp3(+) Treg cells. All T cell IFN-gamma production was also derived from the CD4(+)Foxp3(-) population. Nevertheless, the IL-4Ralpha(-/-)-infected ear dermis, but not draining lymph nodes, consistently displayed 1.5- to 2-fold greater percentages of CD4(+)CD25(+) and CD4(+)Foxp3(+) Treg cells compared with the BALB/c-infected dermis. Thus, CD4(+)Foxp3(-) T cells are a major source of IL-10 that disrupts IFN-gamma activity in L. major-susceptible BALB/c mice. However, the increase in CD4(+)Foxp3(+) T cells within the IL-4Ralpha(-/-) dermis implies a possible IL-10-independent role for Treg cells within the infection site, and may indicate a novel immune escape mechanism used by L. major parasites in the absence of IL-4/IL-13 signaling.

Adoptive transfusion of ex vivo donor alloantigen-stimulated CD4 +CD25 + regulatory T cells ameliorates rejection of DA-to-Lewis rat liver transplantation

Adoptive transfusion of splenocytes from long-term survivors of a tolerance model of rat orthotopic liver transplantation can induce acceptance of liver allografts in a rejection model preconditioned with donor gamma-irradiation before liver transplantation. Recent studies suggest that the regulatory T cells (Treg cells) in splenocytes from long-term survivors play an important role in the induction of liver graft tolerance, but this observation was made from a rejection model preconditioned with donor gamma-irradiation; little is known about the role of Treg cells in liver graft rejection using a naive rejection model. In this study, we examined the therapeutic potential of CD4(+)CD25(+) Treg cells in a naive rejection model of rat liver transplantation. Freshly isolated or ex vivo alloantigen-stimulated CD4(+)CD25(+) Treg cells (1 x 10(6) cells) from naive Lewis RT(1) (LEW) rats were adoptively transferred into another LEW rat on days 1 and 7 after liver transplantation from a Dark Agouti RT1(a) (DA) rat. Recipients were treated with or without oral tacrolimus (FK506) (0.1 mg/kg/day) from days 1 to 7 after transplantation. For ex vivo alloantigen-stimulation, CD4(+)CD25(+) Treg cells from LEW rats were cocultured with mitomycin C-treated DA (donor alloantigen specific) or Brown Norway (BN)(RT1(n), third party) splenocytes for 72 hours. Ex vivo alloantigen-specific CD4(+)CD25(-) T-cell proliferation responses were assessed with fresh and stimulated CD4(+)CD25(+) Treg cells. Freshly isolated, donor alloantigen-stimulated and third-party alloantigen- stimulated CD4(+)CD25(+) Treg cells suppressed antigen-specific CD4(+)CD25(-) T-cell proliferation ex vivo, and adoptive transfusion of these 3 kinds of CD4(+)CD25(+) Treg cells prolonged survival of the liver allografts. The group transfused with the donor alloantigen-stimulated CD4(+)CD25(+) Treg cells had the greatest mean survival among the 3 groups (fresh Treg cells, 21 +/- 2 days, n = 6; third-party alloantigen-stimulated Treg cells, 20 +/- 2 days, n = 6; donor alloantigen-stimulated Treg cells, 30 +/- 2 days, n = 6). When combined with short-term tacrolimus administration, adoptive transfusion of donor antigen-stimulated Treg cells induced the greatest survival time in recipients (greater than 60 days; n = 6). Adoptive transfusion of ex vivo donor alloantigen-stimulated CD4(+)CD25(+) Treg cells combined with short-term tacrolimus treatment may represent a new strategy for preventing rejection after liver transplantation.

What's new in photoimmunology?

What's new in photoimmunology?

Cell surface markers of regulatory T cells are not associated with increased forkhead box p3 expression in blood CD4+ T cells from HIV‐infected patients responding to antiretroviral therapy

Regulatory T (Treg) cells may attenuate host immune responses to pathogens, including HIV and opportunistic pathogens in HIV-infected patients. Treated and untreated progressive HIV disease represent a range of immunological scenarios with potentially different roles for Treg cells. A cell surface marker to determine Treg cell numbers would assist in identifying situations where Treg cells are important. Here we show that levels of Foxp3 mRNA are increased in CD4+ T cells from HIV-infected patients responding to antiretroviral therapy. However, the proportion of peripheral blood CD4+ and CD8+ T cells expressing CD25, neuropilin-1, glucocorticoid-induced TNF receptor and lymphocyte activation gene-3 did not differ as a result of treated or untreated HIV infection when compared with HIV-seronegative controls. Hence, none of the putative Treg cell surface markers identified T-cell populations in peripheral blood that mirrored the effects of HIV infection and antiretroviral therapy on Foxp3 expression.

Maintenance of CD8+T-cell anergy by CD4+CD25+ regulatory T cells in chronic graft-versus-host disease

In a murine model of systemic lupus erythematosus (SLE)-like chronic graft-versus-host disease (cGVHD), donor CD8+ T cells rapidly fall into anergy to host cells, while donor CD4+ T cells hyperactivate B cells and break B-cell tolerance to self-Ags in the recipient mouse. The functional recovery of donor CD8+ T cells can result in the conversion of cGVHD to acute GVHD (aGVHD), indicating that donor CD8+ T-cell anergy is a restriction factor in the development of cGVHD. In this report, we present evidence that donor CD4+CD25+ regulatory T cells (Treg cells) are critical in maintaining the donor CD8+ T-cell anergy and thus suppressing the development of aGVHD in mice that are naturally prone to cGVHD. Our results provide a novel insight into the role of Treg cells in determining cGVHD versus aGVHD.

DMRT1/Dmrt1, the Sex Determining or Sex Differentiating Gene in Vertebrata

Although the phenomenon of sexual dimorphism is widespread in vertebrates, the molecular mechanism of sex-determination is not the same across animal phyla, in contrast to other areas of developmental biology. Recent extensive studies, however, have given proof of evolutionarily conserved function in genes which share a novel DNA binding DM domain, primarily identified in two invertebrate sex regulatory genes: doublesex of Drosophila melanogaster and mab-3 of Caenorhabditis elegans. Their mammalian autosomal homologue, DMRT1, first isolated in humans, was further discovered in genomes of various vertebrate species and appears to be involved in similar aspects of sexual development. Its precise role is still speculated, thus identification of sex reversal mutations, functional studies as well as determination of the sex-specific expression profile during embryogenesis are still being undertaken. Is this a sex determining rather than a sex differentiating gene? Is it involved in a dosage-sensitive mechanism? On what level does it function in the hierarchy of the sexual regulatory gene cascade? Recent results are discussed in this paper.

Dominant tolerance: activation thresholds for peripheral generation of regulatory T cells

In recent years, regulatory T (Treg) cells have reached centre-stage in immune tolerance research. A role for Treg cells in preventing autoimmunity or generating transplantation tolerance is now undisputed. However, in spite of a surge in publications dedicated to Treg cells, surprisingly little is known about their induction, biology and mechanisms of action. In this Opinion, we discuss the facts and the controversies regarding their role in transplantation tolerance. We suggest that peripheral generation of Treg cells, crucial for the generation of dominant transplantation tolerance, might be a consequence of sustained suboptimal antigenic stimulation, and that transforming growth factor-β (TGF-β) might contribute to this process by increasing the threshold for T-cell activation.

Autoreactive T cells persist in rats protected against experimental autoimmune encephalomyelitis and can be activated through stimulation of innate immunity.

Lewis rats can be rendered unresponsive to experimental autoimmune encephalomyelitis by immunization with myelin basic protein (MBP), or MBP68-86, the dominant encephalitogenic MBP epitope for this strain, administered in IFA. However, protected rats harbor potentially encephalitogenic T cells, which are maintained in an inactive state. We investigated whether these quiescent effector cells could be activated in vitro. Although these T cells respond poorly to MBP68-86, they proliferate vigorously whether cocultured with MBP68-86 and either IL-2 or IL-12, suggesting that the T cells are in a state of anergy. Moreover, we could activate these anergic T cells with peptide and cytosine-guanine dinucleotide (CpG) oligonucleotide, but not control oligonucleotide, suggesting that products of the innate immune response are capable of activating anergic autoreactive T cells. The activated T cells produced the proinflammatory cytokine, IFN-gamma in response to IL-12, and IL-6 was secreted in response to CpG oligonucleotide. IL-6 has been reported to play a role in T cell activation by blocking T regulatory/suppressor (Treg) cell-mediated suppression through a Toll-like receptor-dependent pathway. However, anti-IL-6 mAb did not block CpG activation of the anergized cells. In contrast, anti-TGF-beta(1) Ab released the unresponsive T cells from the anergic state in the presence of MBP68-86, whereas TGF-beta(1) inhibited proliferation of MBP68-86- plus CpG-activated T cells. Because TGF-beta(1) has previously been implicated in Treg activity, this finding is consistent with a role for Treg cells in maintaining autoreactive T cells in the anergic state.

Increased frequency of CTLA4 + TGFβ + CD4 + CD25 + T cells in peripheral blood of patients with chronic lymphatic leukemia and multiple myeloma

A globally suppressed T cell function has been described for cancer patients including patients with chronic lymphatic leukemia (CLL) or multiple myeloma (MM). This has been mainly associated with inhibitory factors released by the tumor cells, while the role of recently characterized regulatory immune cells is not understood. Several different regulatory T cells such as CD4+ CD25+ T cells (Treg), TGFβ producing TH3 or IL-10 producing TR1 cells have been described in murine models, and Treg cells have also been implicated in the control of graft versus host disease after allogeneic transplantation in humans. In contrast, little is known about frequencies and function of regulatory cells in leukemias and lymphomas. To address this issue we have analyzed 82 peripheral blood samples from 24 CLL patients, 18 MM patients and 26 healthy individuals. By assessing CD4+ CD25+ T cells we established a strongly significant increase of this subpopulation in both CLL (13 ± 7% mean ± SD, p < 0.01) and MM (13 ± 9%, p < 0.01) when compared to healthy individuals (3.5 ± 1.5%). While CDC4+ CD25+ T cells could also comprise previously activated T cells, the expression of CTLA4 has been associated with Treg cells. In fact, 80± 14% respectively 67± 26% of CD4+ CD25+ T cells in CLL resp. MM were also CTLA4+, while only 30 ± 22% were found to be positive in healthy individuals strongly suggesting that these cells are mainly Treg cells. In contrast, using the BDCA-4 specific antibody for Neuropilin-1, we were unable to detect this molecule recently described on murine Treg cells on any of our samples. Interestingly, a significant proportion of CD4+ CD25+ T cells in CLL 28 ± 13% and MM 22 ± 12% also expressed intracellular TGFβ, which was only found in 6 ± 4% of these T cells in healthy individuals. Whether TGFβ production reflects a particular activation status of Treg cells or whether these cells are a defined subpopulation requires further investigation. By analyzing co-expression of CCR7 and CD45RA we established that the fraction of CD4+ CD25+ T cells was particularly increased in the naive and the central memory pool in peripheral blood of CLL and MM patients. Next we assessed T cell activation as a function of Treg cells. As expected, there was already a significantly decreased proliferative response of CD4+ T cells in many CLL patients even when CD25+ cells were depleted. These findings are most likely explained by chronic exposure to inhibitory cytokines as well as Treg cells. However, even under these conditions, coculture experiments of CD4+ CD25and CD4+ CD25+ Treg cells supported the inhibitory role of Treg cells in CLL. We therefore propose that immunotherapy in any malignancy including CLL and MM characterized by an increase of regulatory factors and cells will significantly benefit from strategies inhibiting immune repression. from Association for Immunotherapy of Cancer: Cancer Immunotherapy – 2nd Annual Meeting Mainz, Germany, 6–7 May 2004

Control of experimental inflammatory bowel disease by regulatory T cells.

A helper T cell type 1-mediated colitis driven by enteric bacteria develops in severe combined immunodeficient mice after transfer of CD45RB(high)CD4(+) T cells. Development of disease can be prevented by cotransfer of the reciprocal CD45RB(low) subset. Analysis of the mechanism of immune suppression transferred by CD45RB(low)CD4(+) cells revealed essential roles for both IL-10 and TGF-beta. These data indicate that a functionally specialized population of regulatory T (Treg) cells exists in normal mice and that these can prevent the development of pathogenic responses toward commensal bacteria. The role of Treg cells in the control of the immune response is discussed.