CD4~+CD25~+调节性T细胞在临床中的应用

CD4+CD25+调节性T细胞(regulatory T cell,Treg)是近年来发现的一类能够抑制免疫应答的重要调节性免疫细胞。近年来,因其在自身免疫性疾病、肿瘤免疫及器官移植耐受诱导中具有广泛的应用前景而备受瞩目。本文就CD4+CD25+Treg的分类、来源、特征及在人类疾病中的临床应用进行综述。     

CD4~+CD25~+调节性T细胞与肿瘤免疫研究进展

调节性T细胞(Treg)是一类具有免疫调节功能的细胞群,在机体的免疫耐受中起着关键性作用。它们主要通过细胞-细胞直接接触的方式抑制CD4+和CD8+效应性T细胞的活化和增殖,来调节获得性免疫系统,阻止自身免疫疾病的发生。Treg中以自然产生的CD4+CD25+调节性T细胞(固有Treg细胞)研究最多。在人类,调控效能主要限于CD4+CD25high亚型。由于Treg独特的生物学功能,它在自身免疫性疾病的发生、移植耐受和肿瘤的发生和转归上越来越受到重视。该文就该类细胞的特点及其与肿瘤关系的研究进展作一综述。     

CD4~+CD25~+调节性T细胞在病毒感染中的免疫调节机制

CD4+CD25+调节性T细胞的主要功能是抑制自身反应性T细胞,主要通过细胞与细胞间直接接触和分泌抑制性细胞因子发挥作用,其在维持机体T细胞内环境稳定、调节和保持对自身抗原耐受之间的平衡以及移植免疫耐受方面具有重要作用。新近研究发现,CD4+CD25+Treg数量和功能异常与病毒感染性疾病的发生、发展关系密切。本文就CD4+CD25+Treg作用机制及其在病毒感染性疾病中的作用进行综述。     

CD4~+CD25~+ Treg细胞与移植免疫耐受

诱导器官移植受者对供者抗原的免疫耐受是防治同种异型移植排斥反应的最理想途径。目前认为,免疫耐受形成的主要机制包括:胸腺及骨髓阴性选择引起的克隆清除(Clonal deletion)、组织特异性自身抗原低表达引起的克隆忽视(Clonal ignorance)、阻断T细胞共刺激信号引起的克隆无能(Clonal anergy)、嵌合体(Chimerism)的形成、调节性T细胞(Regulatory Tcell,Treg)介导的克隆抑制(Clonal suppression)等。近年来CD4+CD25+ Treg细胞的研究已成为免疫学界的热门课题之一。已知CD4+CD25+ Treg细胞存在于小鼠、大鼠和人体中,是机体自然存在的具有主动调节活性的T细胞,对维持自我耐受和控制自身免疫病发挥着重要作用。本文着重就CD4+CD25+ Treg细胞的免疫调节机制及其在诱导移植免疫耐受方面的研究进展做一综述。     

CD4~+ CD25~+调节性T细胞与肿瘤免疫的研究进展

CD4+CD25+调节性T细胞是CD4+T细胞的一个重要亚群,具有免疫抑制和免疫无能两大功能。CD4+CD25+T细胞与自身免疫性疾病的发生、移植耐受具有密切关联。近几年的研究表明,CD4+CD25+T细胞与肿瘤的发生发展和转归亦有着密切联系。本文就调节性T细胞的作用机制及特点与肿瘤免疫的关系作一综述。     

CD4+CD25+调节性T细胞

调节性T细胞(regulatory T cells,Treg)是机体维持自身耐受的重要组成部分。CD4^ CD25^ Treg细胞来源于胸腺,其主要功能是抑制自身反应性T细胞,并且其作用是通过直接的Treg-T效应细胞之间的相互接触方式来实现的。CD4^ CD25^ Treg细胞可分泌多种抑制性细胞因子,但与其抑制功能关系并不明确,目前有证据表明GITR和Foxp3与CD4^ CD25^ Treg细胞的抑制功能有关,并且Foxp3已作为CD4^ CD25^ Treg细胞的特异性标志。通过IL-10、TGF-β等抑制性细胞因子、imDC以及转基因技术可以产生具有免疫抑制功能的调节性T细胞。调节性T细胞在免疫相关性疾病、肿瘤免疫和抗感染免疫等方面具有重要意义。     

CD4+CD25+ 调节性T 细胞与冠状动脉粥样硬化病变的研究进展

CD4+CD25+调节性T细胞是一个具有独特免疫调节功能的T细胞亚群,人体主要通过CD4+CD25+调节性T细胞以免疫负向调节的方式来抑制自身反应性T细胞的作用,减少免疫性疾病的发生,从而维持机体内环境的稳定,维持免疫耐受。CD4+CD25+Treg已被证实其与肿瘤、感染、自身免疫病、移植免疫等多种疾病的发生、发展及转归均相关。随着社会的进步和人民生活水平的提高冠状动脉粥样硬化性病变作为一种慢性病变,其发病率越来越高,已经成为严重危害人类健康的常见病,近年来越来越多的证据表明炎症及免疫反应机制在冠状动脉粥样硬化性心脏病的发生、发展及预后过程中具有重要的作用。而CD4+CD25+调节性T细胞在冠状动脉粥样硬化性病变中所起的作用也受到越来越多的关注。本文就CD4+CD25+调节性T细胞与冠状动脉粥样硬化病变之间的关联做一综述。     

SLE带状疱疹患者外周血CD4~+CD28~+和CD4~+CD25~+FoxP3~+调节性T细胞的表达及相关性研究

目的:检测系统性红斑狼疮(systemic lupus erythematosus,SLE)合并带状疱疹患者外周血CD4~+CD28~+和CD4~+CD25~+Fox P3~+调节性T细胞的表达及相关性,探讨其在SLE合并带状疱疹发病中的临床意义。方法:采用流式细胞术检测30例SLE患者、30例SLE合并带状疱疹患者及30例健康对照者外周血中CD4~+/CD8~+T淋巴细胞亚群表面CD28的表达及CD4~+CD25~+Fox P3~+Treg细胞的表达水平,并分析SLE合并带状疱疹患者外周血CD4~+CD28~+和CD4~+CD25~+Fox P3~+调节性T细胞表达的相关性。结果:SLE合并带状疱疹组患者急性期外周血CD4~+T淋巴细胞比率、绝对计数显著降低,CD4~+、CD8~+T淋巴细胞表面的CD28表达下调,CD4~+CD25~+Fox P3~+Treg细胞水平显著高于SLE组及健康对照组,SLE合并带状疱疹组患者外周血CD4~+CD25~+Fox P3~+Treg水平与CD4~+CD28~+水平成负相关(P均0.05)。结论:SLE合并带状疱疹患者CD4~+、CD8~+T细胞活化异常,CD4~+CD25~+Fox P3~+Treg细胞可能参与抑制了T细胞的活化。     

CD4~+CD25~+调节性T细胞与艾滋病疾病进展的关系概论

艾滋病是全球流行的一种严重传染病,严重损害机体免疫系统,病死率高,至今仍无治愈手段。该病以破环细胞免疫功能为主,因此,认识疾病病程的免疫状态对于进一步探索治疗艾滋病的方法意义重大。CD4+CD25+调节性T细胞在感染性疾病、移植耐受、自身免疫等疾病中的免疫作用是近年来研究热点。在艾滋病中,CD4+CD25+调节性T细胞发挥着重要的免疫作用,研究在不同疾病阶段该细胞亚群所起作用将有助于我们揭示疾病免疫机制。本文概述了CD4+CD25+调节性T细胞频率与艾滋病疾病进展的关系。     

影响CD4+CD25+T细胞分化发育的细胞分子机制

免疫耐受的精髓即机体对外界病原体抗原产生免疫应答的同时对自身抗原不应答.近两年对CD4 CD25 调节性T细胞(CD4 CD25 regulatory T cell, Treg)所发挥的免疫耐受功能的研究取得了令人瞩目的长足进展,对此群细胞所具有的维持外周免疫耐受的独特地位已无可争议.但调节性T细胞的多种生物学特征特别是Treg细胞分化发育的分子机制与信号需求并不清楚,因此探索有关Treg的发生发育及其影响机制已成为近两年研究Treg细胞的热点.综述最近的相关研究数据,了解胸腺以及外周影响Treg细胞分化发育和功能产生的多种细胞分子机制,有助于进一步研究此群细胞的功能及其在抑制自身免疫性疾病、诱导移植耐受等方面的应用.     

APL1, an altered peptide ligand derived from human heat-shock protein 60, increases the frequency of Tregs and its suppressive capacity against antigen responding effector CD4 + T cells from rheumatoid arthritis patients

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by a chronic relapsing-remitting joint inflammation. Perturbations in the balance between CD4?+?T cells producing IL-17 and CD4?+?CD25^highFoxP3?+?Tregs correlate with irreversible bone and cartilage destruction in RA. APL1 is an altered peptide ligand derived from a CD4+ T-cell epitope of human HSP60, an autoantigen expressed in the inflamed synovium, which increases the frequency of CD4?+?CD25^highFoxP3+ Tregs in peripheral blood mononuclear cells from RA patients. The aim of this study was to evaluate the suppressive capacity of Tregs induced by APL1 on proliferation of effector CD4+ T cells using co-culture experiments. Enhanced Treg-mediated suppression was observed in APL1-treated cultures compared with cells cultured only with media. Subsequent analyses using autologous cross-over experiments showed that the enhanced Treg suppression in APL1-treated cultures could reflect increased suppressive function of Tregs against APL1-responsive T cells. On the other hand, APL1-treatment had a significant effect reducing IL-17 levels produced by effector CD4+ T cells. Hence, this peptide has the ability to increase the frequency of Tregs and their suppressive properties whereas effector T cells produce less IL-17. Thus, we propose that APL1 therapy could help to ameliorate the pathogenic Th17/Treg balance in RA patients.     

Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients

CD4+CD25+FOXP3+ T regulatory cells (Tregs) are pivotal for the induction and maintenance of peripheral tolerance in both mice and humans. Rapamycin has been shown to promote tolerance in experimental models and to favor CD4+CD25+ Treg-dependent suppression. We recently reported that rapamycin allows in vitro expansion of murine CD4+CD25+FoxP3+ Tregs, which preserve their suppressive function. In the current study, we show that activation of human CD4+ T cells from healthy subjects in the presence of rapamycin leads to growth of CD4+CD25+FOXP3+ Tregs and to selective depletion of CD4+CD25- T effector cells, which are highly sensitive to the antiproliferative effect of the compound. The rapamycin-expanded Tregs suppress proliferation of both syngeneic and allogeneic CD4+ and CD8+ T cells. Interestingly, rapamycin promotes expansion of functional CD4+CD25+FOXP3+ Tregs also in type 1 diabetic patients, in whom a defect in freshly isolated CD4+CD25+ Tregs has been reported. The capacity of rapamycin to allow growth of functional CD4+CD25+FOXP3+ Tregs, but also to deplete T effector cells, can be exploited for the design of novel and safe in vitro protocols for cellular immunotherapy in T cell-mediated diseases.     

Experience-driven development: effector/memory-like alphaE+Foxp3+ regulatory T cells originate from both naive T cells and naturally occurring naive-like regulatory T cells

Naturally occurring Foxp3+CD25+CD4+ regulatory T cells (Treg) have initially been described as anergic cells; however, more recent in vivo studies suggest that Tregs vigorously proliferate under both homeostatic as well as inflammatory conditions. We have previously identified a subset of murine CD4+ Tregs, which is characterized by expression of the integrin alphaEbeta7 and which displays an effector/memory-like phenotype indicative of Ag-specific expansion and differentiation. In the present study, the alphaE+ Treg subset was found to contain a large fraction of cycling cells under homeostatic conditions in healthy mice. Using an adoptive transfer system of Ag-specific T cells, we could demonstrate that the vast majority of transferred natural, naive-like CD25+CD4+ Tregs acquired expression of the integrin alphaEbeta7 upon tolerogenic application of Ag via the oral route. In addition, using the same system, Foxp3+ Tregs could be de novo induced from conventional naive CD25-CD4+ T cells, and this conversion was associated with concomitant expression of alphaE. These findings suggest that Tregs expressing the integrin alphaE are effector/memory Tregs with a high turnover rate that can develop in the periphery upon Ag contact under tolerogenic conditions, both from thymic-derived CD25+CD4+ Tregs with a naive-like phenotype as well as from conventional naive T cells.     

CD8+CD45RA+CCR7+FOXP3+ T Cells with Immunosuppressive Properties: A Novel Subset of Inducible Human Regulatory T Cells

CD8 T cells stimulated with a suboptimal dose of anti-CD3 Abs (100 pg/ml) in the presence of IL-15 retain a naive phenotype with expression of CD45RA, CD28, CD27, and CCR7 but acquire new functions and differentiate into immunosuppressive T cells. CD8(+)CCR7(+) regulatory T cells (Tregs) express FOXP3 and prevent CD4 T cells from responding to TCR stimulation and entering the cell cycle. Naive CD4 T cells are more susceptible to inhibition than memory cells. The suppressive activity of CD8(+)CCR7(+) Tregs is not mediated by IL-10, TGF-β, CTLA-4, CCL4, or adenosine and relies on interference with very early steps of the TCR signaling cascade. Specifically, CD8(+)CCR7(+) Tregs prevent TCR-induced phosphorylation of ZAP70 and dampen the rise of intracellular calcium in CD4 T cells. The inducibility of CD8(+)CCR7(+) Tregs is correlated with the age of the individual with PBLs of donors older than 60 y yielding low numbers of FOXP3(low) CD8 Tregs. Loss of CD8(+)CCR7(+) Tregs in the elderly host may be of relevance in the aging immune system as immunosenescence is associated with a state of chronic smoldering inflammation.     

CD4+CD25high T cells are enriched in the tumor and peripheral blood of prostate cancer patients

In this study, we investigated whether CD4+CD25high regulatory T cells (Treg) are increased in the tumor tissue and peripheral blood of early-stage prostate cancer patients undergoing prostatectomy. We show that the prevalence of CD4+CD25high T cells inside the prostate was significantly higher in the tumor compared with benign tissue from the same prostate. Furthermore, the frequency of CD4+CD25high T cells in peripheral blood was significantly higher in prostate cancer patients compared with normal donors. A proportion of the CD4+CD25high T cells was also shown to be glucocorticoid-induced TNF receptor, ICOS, and FOXP3 positive. Moreover, CD4+CD25+ T cells from blood and supernatants from cultured prostate tumor tissue samples exhibited immunosuppressive function in vitro. Furthermore, supernatants from cultured prostate tissue samples and prostate cancer ascites fluid induced migration of CD4+CD25+ T cells and were shown to contain the regulatory T cell chemokine CCL22 by ELISA. Our findings indicate that Tregs are an important cellular component of early-stage prostate tumors, and thus new therapeutic strategies aimed at inhibition or depletion of Tregs may improve prostate cancer immunotherapy.     

T regulatory cells: aid or hindrance in the clearance of disease?

CD4+ CD25+ T regulatory cells (Tregs) are classified as a subset of T cells whose role is the suppression and regulation of immune responses to self and non-self. Since their discovery in the early 1970s, the role of CD4+ CD25+ Tregs in both autoimmune and infectious disease has continued to expand. This review examines the recent advances on the role CD4+ CD25+ Tregs may be playing in various diseases regarding progression or protection. In addition, advances made in the purification and manipulation of CD4+ CD25+ Tregs using new cell markers, techniques and antibodies are discussed. Ultimately, an overall understanding of the exact mechanism which CD4+ CD25+ Tregs implement during disease progression will enhance our ability to manipulate CD4+ CD25+ Tregs in a clinically beneficial manner.     

Increased natural CD4+CD25+ regulatory T cells and their suppressor activity do not contribute to mortality in murine polymicrobial sepsis

Regulatory T cells (Tregs), including natural CD4+CD25+ Tregs and inducible IL-10 producing T regulatory type 1 (T(R)1) cells, maintain tolerance and inhibit autoimmunity. Recently, increased percentages of Tregs have been observed in the blood of septic patients, and ex vivo-activated Tregs were shown to prevent polymicrobial sepsis mortality. Whether endogenous Tregs contribute to sepsis outcome remains unclear. Polymicrobial sepsis, induced by cecal ligation and puncture, caused an increased number of splenic Tregs compared with sham-treated mice. Splenic CD4+CD25+ T cells from septic mice expressed higher levels of Foxp3 mRNA and were more efficient suppressors of CD4+CD25- T effector cell proliferation. Isolated CD4+ T cells from septic mice displayed increased intracellular IL-10 staining following stimulation, indicating that T(R)1 cells may also be elevated in sepsis. Surprisingly, Ab depletion of total CD4+ or CD4+CD25+ populations did not affect mortality. Furthermore, no difference in survival outcome was found between CD25 or IL-10 null mice and wild-type littermates, indicating that Treg or T(R)1-generated IL-10 are not required for survival. These results demonstrate that, although sepsis causes a relative increase in Treg number and increases their suppressive function, their presence does not contribute significantly to overall survival in this model.     

CD4+CD25+ regulatory T cells inhibit the antigen-dependent expansion of self-reactive T cells in vivo

A deficiency of CD4+CD25+ regulatory T cells (CD25+ Tregs) in lymphopenic mice can result in the onset of autoimmune gastritis. The gastric H/K ATPase alpha (H/Kalpha) and beta (H/Kbeta) subunits are the immunodominant autoantigens recognized by effector CD4+ T cells in autoimmune gastritis. The mechanism by which CD25+ Tregs suppress autoimmune gastritis in lymphopenic mice is poorly understood. To investigate the antigenic requirements for the genesis and survival of gastritis-protecting CD25+ Tregs, we analyzed mice deficient in H/Kbeta and H/Kalpha, as well as a transgenic mouse line (H/Kbeta-tsA58 Tg line 224) that lacks differentiated gastric epithelial cells. By adoptive transfer of purified T cell populations to athymic mice, we show that the CD25+ Treg population from mice deficient in either one or both of H/Kalpha and H/Kbeta, or from the H/Kbeta-tsA58 Tg line 224 mice, is equally effective in suppressing the ability of polyclonal populations of effector CD4+ T cells to induce autoimmune gastritis. Furthermore, CD25+ Tregs, from either wild-type or H/Kalpha-deficient mice, dramatically reduced the expansion of pathogenic H/Kalpha-specific TCR transgenic T cells and the induction of autoimmune gastritis in athymic recipient mice. Proliferation of H/Kalpha-specific T cells in lymphopenic hosts occurs predominantly in the paragastric lymph node and was dependent on the presence of the cognate H/Kalpha Ag. Collectively, these studies demonstrate that the gastritis-protecting CD25+ Tregs do not depend on the major gastric Ags for their thymic development or their survival in the periphery, and that CD25+ Tregs inhibit the Ag-specific expansion of pathogenic T cells in vivo.