CD4+CD25+调节性T细胞及相关细胞因子的研究进展

胸腺来源的CD4^＋CD25^＋调节性T细胞（Treg）是机体维持自身免疫耐受的重要组成部分，约占CD4^＋T细胞的5％-10％。它具有免疫抑制及免疫无能的特性，是最重要的Treg细胞的亚群之一。近年发现CD4^＋CD25^＋Treg细胞主要通过分泌一些抑制性细胞因子和抑制自身反应性T细胞的免疫应答等方式在维持自身免疫耐受中扮演着重要的角色，其数量的缺乏或功能紊乱会导致各种自身免疫性疾病的发生。     

CD4+CD25+调节性T细胞的生物学特性及功能

对自身抗原产生免疫耐受是防止发生自身免疫病的关键。自1995年日本学者Sakaguchi等首次报道CD4^＋CD25^＋调节性T（Treg）细胞以来，越来越多的研究证明这群T细胞在自身耐受的维持中发挥着重要的作用。CD4^＋CD25^＋调节性T细胞具有以下特点：①自身免疫防御作用；②自然条件下是处于无能（Anergy）状态；③抑制其他CD4^＋T细胞和CD8^＋T细胞的生物活性；④抑制活性是抗原非特异性的；⑤抑制方法可能通过细胞与细胞间直接接触，或经分泌抑制性细胞因子发挥免疫抑制效应；     

CD4+CD25+调节性T细胞在母-胎免疫耐受中的作用

CD4^＋CD25^＋调节性T细胞（Regulatory T cell，Treg）是最近被人们认识的一类重要的具有免疫调节功能的T细胞亚群，其功能障碍可能与自身免疫性疾病密切相关；并且参与维持外周T细胞内环境稳定；在移植耐受中其也起着关键作用。近年研究发现，在妊娠的各个时期，母体外周血、     

Foxp3和CD4^＋ CD25^＋ 调节性T细胞研究进展

调节性T细胞是机体维持自身耐受的重要组成部分，其对免疫反应具有抑制效应，在体外增殖能力低，在免疫病理、移植物耐受、阻止自身免疫反应和维持机体免疫平衡方面都有一定作用。最近发现Foxp3在调控调节性T细胞的一重要亚群CD4^ CD25^ 细胞的发育上起很重要的作用。本文就CD4^ CD25^ 细胞特性、Foxp3在其发育和功能发挥中的作用以及其活性调节方面作一综述。     

CD4~+CD25~+ Treg的免疫调节作用机制以及临床研究进展

CD4+CD25+调节性T细胞(CD4+CD25+Treg)是一个具有独特免疫调节功能的T细胞亚群,它不仅能够抑制自身免疫性疾病的发生,而且可能参与诱导移植耐受以及肿瘤免疫的调节,在维持机体内环境的稳定中起重要作用。文章旨在对近两年关于CD4+CD25+Treg的免疫调节作用机制以及临床研究进展作一综述。     

CD4~＋ CD25~＋ Foxp3~＋调节性T细胞与自身免疫性疾病

自身免疫性疾病系由于机体免疫系统失衡,产生针对自身组织的免疫应答并导致自身组织、器官损害的一类疾病。调节性T淋巴细胞（regulatory T cell,Treg）具有免疫应答低下和免疫抑制特性,在维持机体免疫耐受和免疫应答稳态方面具有非常重要的作用,Treg的异常与多种自身免疫性疾病有关[1]。Foxp3特异性表达于CD4＋CD25＋Treg细胞,与其发育、成熟以及抑制功能关系密切。但是目前关于该转录因子的表达调控机制却不清楚。本文拟就CD4＋CD25＋Foxp3 Treg细胞的研究进展及与多种自身免疫性疾病的关系作一综述。     

CD4^＋CD25^＋T细胞与移植免疫耐受

调节性T细胞是机体维持自身耐受的重要组成部分.CD4^＋CD25^＋T细胞以持续高表达CD25为特征,可通过细胞间直接接触或分泌TGF-β、IL-10来发挥抑制功能.它广泛参与自身免疫耐受、肿瘤免疫、移植免疫.现就其发育、特性、发挥功能的机制以及在移植免疫耐受中的作用和应用前景作一综述.     

转化生长因子-β参与CD4^＋CD25^＋调节性T细胞诱导的发育研究进展

CD4^＋CD25^＋调节性T细胞（CD4^＋CD25^＋Treg）足一类具有免疫调节功能的淋巴细胞,在维持机体免疫耐受和免疫应答稳态方面发挥重要作用。转化生长因子β（TGF—β）与CD4^＋CD25^＋Treg的发育分化和功能有着密不可分的关系,虽然作用机理尚不完全明了,但其重要性毋情置疑。     

Foxp3和CD4+CD25+调节性T细胞研究进展

调节性T细胞是机体维持自身耐受的重要组成部分,其对免疫反应具有抑制效应,在体外增殖能力低,在免疫病理、移植物耐受、阻止自身免疫反应和维持机体免疫平衡方面都有一定作用.最近发现Foxp3在调控调节性T细胞的一重要亚群CD4+CD25+T细胞的发育上起很重要的作用.本文就CD4+CD25+T细胞特性、Foxp3在其发育和功能发挥中的作用以及其活性调节方面作一综述.     

CD4^＋CD25^＋调节性T细胞及其功能

CD4^＋CD25^＋T细胞亚群具有免疫调节功能，是机体内调节性T细胞（regulatory T cells，Tr）的主要类型，于1995年首次由Sakaguchi等提出。CD4^＋CD25^＋Tr的免疫学特点是免疫无反应性和免疫抑制性，可以通过下调机体的免疫应答维持对自身和非自身抗原的免疫耐受，CD4^＋CD25^＋Tr数量低下和功能紊乱可导致多种自身免疫性疾病，另外，它们在某些严重的炎症性疾病和下调肿瘤免疫应答中也起重要作用。对这类细胞生物特性的深入研究将有助于我们对临床有关疾病机制的理解及新型治疗策略的制定。     

Alterations of peripheral CD4+CD25+Foxp3+ T regulatory cells in mice with STZ-induced diabetes

Complications arising from abnormal immune responses are the major causes of mortality and morbidity in diabetic patients. CD4+CD25+T regulatory cells (Tregs) play pivotal roles in controlling immune homeostasis, immunity and tolerance. The effect of hyperglycemia on CD4+CD25+Tregs has not yet been addressed. Here we used streptozotocin (STZ)-induced diabetic mice to study the effects of long-term hyperglycemia on CD4+CD25+Tregs in vivo. Four months after the onset of diabetes, the frequency of CD4+CD25+Foxp3+ T regulatory cells was significantly elevated in the spleen, peripheral blood lymphocytes (PBLs), peripheral lymph nodes (pLNs) and mesenteric LNs (mLNs). CD4+CD25+Tregs obtained from mice with diabetes displayed defective immunosuppressive functions and an activated/memory phenotype. Insulin administration rescued these changes in the CD4+CD25+ Tregs of diabetic mice. The percentage of thymic CD4+CD25+ naturally occurring Tregs (nTregs) and peripheral CD4+Helios+Foxp3+ nTregs were markedly enhanced in diabetic mice, indicating that thymic output contributed to the increased frequency of peripheral CD4+CD25+Tregs in diabetic mice. In an in vitro assay in which Tregs were induced from CD4+CD25- T cells by transforming growth factor (TGF)-β, high glucose enhanced the efficiency of CD4+CD25+Foxp3+ inducible Tregs (iTregs) induction. In addition, CD4+CD25- T cells from diabetic mice were more susceptible to CD4+CD25+Foxp3+ iTreg differentiation than those cells from control mice. These data, together with the enhanced frequency of CD4+Helios-Foxp3+ iTregs in the periphery of mice with diabetes, indicate that enhanced CD4+CD25+Foxp3+ iTreg induction also contributes to a peripheral increase iCD4+CD25+Tregs in diabetic mice. Our data show that hyperglycemia may alter the frequency of CD4+CD25+Foxp3+ Tregs in mice, which may result in late-state immune dysfunction in patients with diabetes.     

An MHC-linked locus modulates thymic differentiation of CD4+CD25+Foxp3+ regulatory T lymphocytes

CD4+CD25+Foxp3+ regulatory T lymphocytes are crucial for maintenance of immunological tolerance to self and innocuous non-self, are known to modulate immunity to tumors and infectious agents and can induce transplantation tolerance. Surprisingly, only a single genetic polymorphism is known to modulate regulatory T cell (Treg) development in the thymus, leading to a lethal autoimmune disorder. Here, we show that considerably different levels of Tregs are found in the thymi of distinct common laboratory mouse strains. We demonstrate that distinct levels of phenotypically and functionally identical Tregs develop with similar kinetics in the studied mice, that the responsible locus acts in a thymocyte-intrinsic manner and that levels of thymic Foxp3+ Tregs correlate to those found in the periphery. Using several congenic mouse strains, we mapped one of the at least two genetic loci capable of quantitatively modulating thymic Treg development to a 相似文献   

CD4+CD25+ Tregs and NKT cells: regulators regulating regulators

CD4+CD25+ regulatory T cells (Tregs) and natural killer T (NKT) cells are two populations of T lymphocytes that can independently regulate adaptive and innate immune responses. Although most studies have investigated the regulatory properties of these T-cell subsets independently of each other, recent reports have provided evidence for cross-talk between Tregs and NKT cells, and, consequently, the immunoregulatory networks are seen in a new perspective. Activated NKT cells seem to modulate quantitatively and qualitatively Treg function through IL-2-dependent mechanisms, whereas Tregs can suppress the proliferation, cytokine release and cytotoxic activity of NKT cells by cell-contact-dependent mechanisms. Importantly, Tregs and NKT cells share crucial signaling pathways that could be responsible for their concerted responses. The advances in our understanding of the interactions between distinct subsets of regulatory T cells in autoimmunity might unveil new methods for harnessing these cells with immunotherapeutic properties.     

CpG DNA inhibits CD4+CD25+ Treg suppression through direct MyD88-dependent costimulation of effector CD4+ T cells

Toll-like receptor (TLR) ligands are notable for their ability to induce APC maturation, which in turn facilitates optimal T cell mediated immune responses. Toll-like receptor ligands, such as CpG DNA, can also modulate immune responses by blocking the suppressive effects of CD4+CD25+ regulatory T cells (Tregs). Recently, we have demonstrated that CpG DNA, in addition to its actions on APCs and Tregs, can provide direct costimulatory signals to CD4+CD25- T cells. Here we show that this costimulatory effect is sufficient to abrogate suppression by Tregs. These data indicate a previously undefined role for TLR ligands in directly modulating CD4+ T cell responses.     

Use of CFSE to Monitor Ex Vivo Regulatory T-cell Suppression of CD4+ and CD8+ T-cell Proliferation within Unseparated Mononuclear Cells from Malignant and Non-Malignant Human Lymph Node Biopsies

Regulatory T-cells (Tregs) play a critical role in the inhibition of self-reactive immune responses and as such have been implicated in the suppression of anti-tumor immunity. A clearer understanding of the mechanisms by which Tregs suppress effector T-cell responses within the context of anti-tumor immunity may lead to more effective treatments. The study of Tregs, particularly in the context of ongoing active immune responses, has been challenging due to the lack of surface molecules truly unique to these cells. Several surface markers have been shown to be constitutively expressed by Tregs, such as high levels of CD25, GITR and CTLA-4, and thus have been useful for their study. However, the heterogeneity of surface marker expression still makes identifying Tregs ex vivo challenging. As such, the only means available, currently, to accurately identify Tregs ex vivo is through functional suppression assays. Tregs have been shown to inhibit a variety of cellular functions including T-cell proliferation and as such, in vitro inhibition of proliferation is routinely used as a measure of Treg-mediated suppression. Several assays currently exist to assay cellular proliferation, including [³H]thymidine incorporation and CFSE dilution. However, a limitation of using [³H]thymidine is the difficulty differentiating between proliferation of the target cells and that of the Tregs themselves. Due to the ability to differentiate by flow cytometric analysis between labeled and unlabelled cells using CFSE, in contrast to [³H]thymidine, it is possible to analyze the proliferation of labeled target cells separate from unlabeled Tregs in co-culture experiments. In addition, the use of multi-color flow cytometry allows for the analysis of different T-cell subsets simultaneously without the necessity to separate these cells. Thus, CFSE has several advantages to [³H]thymidine for analysis of cellular proliferation. Herein we describe our work utilizing CFSE labeling to assess, (1) proliferative responses of CD4⁺ and CD8⁺ T-cells in unseparated single cell suspensions from human lymph nodes and, (2) the ability of tumor infiltrating suppressive populations, including Tregs, isolated from neoplastic lymph nodes to suppress in vitro proliferation of allogeneic CD4⁺ and CD8⁺ T-cells isolated from peripheral blood of healthy donors.     

Circulating CD4+ CD25+ regulatory T cells correlate with chronic hepatitis B infection

Circulating CD4+ CD25+ regulatory T cells (Tregs) have been demonstrated to maintain immunotolerance and suppress the antigen-specific or antigen-non-specific T-cell responses, but their role in chronic hepatitis B (CHB) infection in humans has not been well characterized. In this study, we analysed the frequency and phenotypic characteristics of CD4+ CD25+ Tregs in patients of different hepatitis B virus (HBV) infection status, and investigated the effect of Tregs on antiviral immune responses in CHB patients, and the mechanism of this effect. A total of 137 subjects, including 79 CHB patients, 26 asymptomatic HBV carriers (ASCs), 12 acute hepatitis B (AHB) patients and 20 healthy controls, were enrolled in the study. We found that the frequency of CD4+ CD25(high) Tregs in AHB patients was comparable to that in healthy controls, while it was significantly increased in CHB patients. CD4+ CD25+ Tregs produced interleukin (IL)-10 but little or no interferon (IFN)-gamma under anti-CD3 stimulation. In CHB patients, the frequency of CD4+ CD25(high) Tregs positively correlated with serum viral load, and the Tregs were capable of suppressing the proliferation and IFN-gamma production of autologous peripheral blood mononuclear cells (PBMC) mediated by HBV antigen stimulation in vitro. However, combined administration of anti-programmed death-1 (PD-1) and anti-cytotoxic lymphocyte antigen-4 (CTLA-4) monoclonal antibody slightly enhanced the cellular proliferation and significantly increased the IFN-gamma production of PBMC cocultured with Tregs at a ratio of 2:1. Thus, the frequency of circulating CD4+ CD25+ Tregs is increased in patients with CHB, and this may play an important role in viral persistence by modulating virus-specific immune responses.     

Antigen-non-specific regulation centered on CD25+Foxp3+ Treg cells

CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Tregs) are of special interest in immunology because of their potent inhibitory function. Many fundamental aspects of Tregs, including their antigenic profile, development and peripheral homeostasis, remain highly controversial. Here, we propose a Treg-centered antigen-non-specific immunoregulation model focused on the T-cell system, particularly on CD4⁺ T cells. The T-cell pool consists of naive T cells (Tnais), Tregs and effector T cells (Teffs). Regardless of antigen specificity, the ratio of the activated T-cell subsets (Treg/Teff/Tnai) and their temporal and spatial uniformity dictate the differentiation of Tnais. Activated Tregs inhibit the activation, proliferation, induction and activity of Teffs; in contrast, activated Teffs inhibit the induction of Tregs from Tnais but cooperate with Treg-specific antigens to promote the proliferation and activity of Tregs. In many cases, these interactions are antigen-non-specific, whereas the activation of both Tregs and Teffs is antigen-specific. Memory T-cell subsets are essential for the maintenance of adaptive immune responses, but the antigen-non-specific interactions among T-cell subsets may be more important during the establishment of the adaptive immune system to a newly encountered antigen. This is especially important when new and memory antigens are presented closely—both temporally and spatially—to T cells, because there are always baseline levels of activated Tregs, which are usually higher than levels of memory T cells for new antigens. Based on this hypothesis, we further infer that, under physiological conditions, Tregs in lymph nodes mainly recognize antigens frequently released from draining tissues, and that these self-reactive Tregs are commonly involved in the establishment of adaptive immunity to new antigens and in the feedback control of excessive responses to pathogens.     

Modulation of monocyte/macrophage function by human CD4+CD25+ regulatory T cells

The suppressive effects of CD4+CD25+ regulatory T cells (Tregs) on T cells have been well documented. Here we investigated whether human CD4+CD25+ Tregs can inhibit the proinflammatory properties of monocytes/macrophages. Monocytes and T cells were isolated from peripheral blood of healthy volunteers by magnetic cell separation and cocultured for 40 h. Monocytes were analyzed directly for cytokine production and phenotypic changes or repurified and used in T-cell stimulation and lipopolysaccharide challenge assays. Coculture with CD4+CD25+ Tregs induced minimal cytokine production in monocytes, whereas coculture with CD4+CD25- T cells resulted in large amounts of proinflammatory (tumor necrosis factor-alpha, interferon-gamma, interleukin-6) and regulatory (interleukin-10) cytokines. Importantly, when these CD4+CD25+ Treg-treated monocytes were repurified after coculture and challenged with lipopolysaccharide, they were severely inhibited in their capacity to produce tumor necrosis factor-alpha and interleukin-6 compared with control-treated monocytes. In addition, monocytes that were precultured with CD4+CD25+ Tregs displayed limited upregulation of human leukocyte antigen class II, CD40 and CD80, and downregulation of CD86 compared with control-treated monocytes. This altered phenotype had functional consequences, as shown by the reduction in T cell-stimulatory capacity of Treg-treated monocytes. Together, these data demonstrate that CD4+CD25+ Tregs can exert direct suppressive effects on monocytes/macrophages, thereby affecting subsequent innate and adaptive immune responses.     

Lower proportions of CD4+CD25high and CD4+FoxP3, but not CD4+CD25+CD127low FoxP3+T cell levels in children with autoimmune thyroid diseases

The essence of autoimmune thyroid disease (AITD) is loss of tolerance of own tissues caused by malfunction of T lymphocytes, which affects the production of antibodies reacting with particular cell structures and tissues. Foxp3⁺ regulatory T cells (Tregs) take part in the regulation of immune response and play a leading role in developing immune tolerance through active suppression. The aim of the study was to estimate the expression of CD4+CD25^high, CD4+CD25+CD127^lowFoxP3⁺ and CD4+ FoxP3 T cells in patients with Graves' disease (GD) (n = 24, median age 15.5 years), in patients with Hashimoto's thyroiditis (HT) (n = 30, median age 15 years) in comparison with sex- and age-matched healthy control subjects (n = 30, median age 15 years). Polychromatic flow cytometry using a FACSCalibur (BD Biosciences) cytometer was applied to delineate T regulatory cell populations. In untreated patients with Graves' disease and HT we observed a significant decrease in CD4+FoxP3 (p < 0.001, p < 0.01) and CD4+CD25^high (p < 0.016, p < 0.048) T lymphocytes as compared to the healthy control subjects. After 6–12 months of L-thyroxine therapy in HT cases these phenotypes of Tregs were normalized, yet no such changes were observed during GD therapy. The analysis of CD4+CD25+CD127^lowFoxP3⁺T cells in the peripheral blood revealed comparable percentages of these cells in patients with thyroid autoimmune diseases to the controls. We conclude that the reduction number of Tregs with CD4+CD25^high and CD4+FoxP3 phenotype suggests their role in initiation and development of autoimmune process in thyroid disorders.     

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.