Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma

Most non-Hodgkin lymphomas (NHLs) are of B-cell origin, but the tumor tissue can be variably infiltrated with T cells. In the present study, we have identified a subset of CD4(+)CD25(+) T cells with high levels of CTLA-4 and Foxp3 (intratumoral T(reg) cells) that are overrepresented in biopsy specimens of B-cell NHL (median of 17% in lymphoma biopsies, 12% in inflammatory tonsil, and 6% in tumor-free lymph nodes; P = .001). We found that these CD4(+)CD25(+) T cells suppressed the proliferation and cytokine (IFN-gamma and IL-4) production of infiltrating CD4(+)CD25(-) T cells in response to PHA stimulation. PD-1 was found to be constitutively and exclusively expressed on a subset of infiltrating CD4(+)CD25(-) T cells, and B7-H1 could be induced on intratumoral CD4(+)CD25(+) T cells in B-cell NHL. Anti-B7-H1 antibody or PD-1 fusion protein partly restored the proliferation of infiltrating CD4(+)CD25(-) T cells when cocultured with intratumoral T(reg) cells. Finally, we found that CCL22 secreted by lymphoma B cells is involved in the chemotaxis and migration of intratumoral T(reg) cells that express CCR4, but not CCR8. Taken together, our results suggest that T(reg) cells are highly represented in the area of B-cell NHL and that malignant B cells are involved in the recruitment of these cells into the area of lymphoma.     

CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25 T cells

Foxp3 expression was initially thought to be restricted to the CD4(+)CD25(+) regulatory T-cell population. However, recent studies suggest that forkhead box P3 (Foxp3) is expressed in CD4(+)CD25(-) T cells in aged mice. In the present study in B-cell non-Hodgkin lymphoma (NHL), we found that a subset of intratumoral but not peripheral blood CD4(+)CD25(-) T cells, comprising about 15% of intratumoral CD4(+) T cells, express Foxp3 and are capable of suppressing the proliferation of autologous infiltrating CD8(+) T cells. In vitro activation with OKT3/anti-CD28 antibody (Ab) or dendritic cells (DCs) induced Foxp3 expression in a subset of these CD4(+)CD25(-)Foxp3(-) T cells. We found that the presence of lymphoma B cells during activation augmented activation-induced Foxp3 expression in CD4(+)CD25(-) T cells. We also found that CD70(+) lymphoma B cells significantly contributed to the activation-induced Foxp3 expression in intratumoral CD4(+)CD25(-) T cells. Furthermore, the blockade of CD27-CD70 interaction by anti-CD70 Ab abrogated lymphoma B-cell-mediated induction of Foxp3 expression in intratumoral CD4(+)CD25(-) T cells. Taken together, these studies reveal a novel role for NHL B cells in the development of intratumoral regulatory T cells.     

Severe immune dysregulation affects CD4(+)CD25(hi)FoxP3(+) regulatory T cells in HIV-infected patients with low-level CD4 T-cell repopulation despite suppressive highly active antiretroviral therapy

We hypothesized that CD4(+)CD25(hi)FoxP3(+) regulatory T cells (Tregs) could be involved in the high immune activation existing in patients with low-level CD4 T-cell repopulation under suppressive high active antiretroviral therapy (hereafter, "LLR patients"). Sixteen LLR patients, 18 human immunodeficiency virus (HIV)-infected controls (hereafter, "HIV controls"), and 16 healthy subjects were included. The frequency of CD4(+)CD25(hi)FoxP3(+) and HIV-specific Treg suppressive function were assessed. Relationships between Treg and CD4/CD8 activation (HLA-DR/CD38) and the frequency of naive CD4 T-cells were assessed. Low-level patients showed a higher Treg frequency but reduced HIV-specific immunosuppressive functions than HIV controls. Whereas in healthy subjects a strong negative correlation between Tregs and activated CD8 T cells emerged (r?=?-0.75, P?相似文献   

CD4+CD25+ regulatory T-cell deficiency in patients with hepatitis C-mixed cryoglobulinemia vasculitis

Patients who are chronically infected with hepatitis C virus (HCV) often develop mixed cryoglobulinemia (MC), a B-cell proliferative disorder with polyclonal activation and autoantibody production. We investigated if MC is associated with a deficit of CD4(+)CD25(+) immunoregulatory T (Treg) cells, which have been shown to control autoimmunity. Because Treg cells express higher amounts of CD25 than activated CD4(+) T cells, we analyzed blood CD4(+)CD25(high) Treg cells in 69 untreated patients chronically infected with HCV. Treg cell frequency in patients without MC (8.8% +/- 2.3%) or with asymptomatic MC (7.4% +/- 2.1%) was comparable to that of healthy controls (7.9% +/- 1.3%). In contrast, it was significantly reduced in symptomatic MC patients (2.6% +/- 1.2%, P <.001) even when compared to a panel of untreated HCV(-) patients with different inflammatory disorders (6.2% +/- 0.8%, P <.0001). In symptomatic MC patients, the purified remaining CD4(+)CD25(+) T cells retained suppressive activity in vitro. These results, together with experimental data showing that depletion of Treg cells induces autoimmunity, suggest a major role of Treg cell deficiency in HCV-MC vasculitis and this is the first report of a quantitative Treg cell deficiency in virus-associated autoimmunity.     

Depletion of CD25^＋CD4^＋T cells （Tregs） enhances the H BV-specific CD8^＋ T cell response primed by DNA immunization

AIM: Persistent hepatitis B virus (HBV) infection is characterized by a weak CD8+ T cell response to HBV. Immunotherapeutic strategies that overcome tolerance and boost these suboptimal responses may facilitate viral clearance in chronically infected individuals. Therefore, we examined whether CD25+CD4+ regulatory T (Treg) cells might be involved in a inhibition of CD8+T cell priming or in the modulation of the magnitude of the 'peak' antiviral CD8+ T cell response primed by DNA immunization. METHODS: B10.D2 mice were immunized once with plasmid pCMV-S. Mice received 500 μg of anti-CD25 mAb injected intraperitoneally 3 d before DNA immunization to deplete CD25+ cells. Induction of HBV-specific CD8+ T cells in peripheral blood mononuclear cells (PBMCs) was measured by S28-39 peptide loaded DimerX staining and their function was analyzed by intracellular IFN-γ staining. RESULTS: DNA immunization induced HBV-specific CD8+ T cells. At the peak T cell response (d 10), 7.1±2.0% of CD8+ T cells were HBV-specific after DNA immunization, whereas 12.7±3.2% of CD8+ T cells were HBV-specific in Treg-depleted mice, suggesting that DNA immunization induced more antigen-specific CD8+ T cells in the absence of CD25+ Treg cells (n = 6, P<0.05). Similarly, fewer HBV specific memory T cells were detected in the presence of these cells (1.3±0.4%) in comparison to Treg-depleted mice (2.6±0.9%) on d 30 after DNA immunization (n - 6, P<0.01). Both IFN-γ production and the avidity of the HBV-specific CD8+ T cell response to antigen were higher in HBV-specific CD8+ T cells induced in the absence of Treg cells. CONCLUSION: CD25+ Treg cells suppress priming and/or expansion of antigen-specific CD8+ T cells during DNA immunization and the peak CD8+ T cell response is enhanced by depleting this cell population. Furthermore, Treg cells appear to be involved in the contraction phase of the CD8+ T cell response and may affect the quality of memory T cell pools. The elimination of Treg cells or their inhibition may be important in immunotherapeutic strategies to control HBV infection by inducing virus-specific cytotoxic T lymphocyte responses in chronically infected subjects.     

FoxP3+CD4+ regulatory T cells play an important role in acute HIV-1 infection in humanized Rag2-/-gammaC-/- mice in vivo

The role of FoxP3(+)CD4(+) regulatory T (Treg) cells in HIV-1 disease in vivo is poorly understood due to the lack of a robust model. We report here that CD4(+)FoxP3(+) T cells are developed in all lymphoid organs in humanized Rag2(-/-)gammaC(-/-) (DKO-hu HSC) mice and they display both Treg phenotype and Treg function. These FoxP3(+) Treg cells are preferentially infected and depleted by a pathogenic HIV-1 isolate in HIV-infected DKO-hu HSC mice; and depletion of Treg cells is correlated with induction of their apoptosis in vivo. When CD4(+)CD25(+/hi) Treg cells are depleted with the IL-2-toxin fusion protein (denileukin diftitox), HIV-1 infection is significantly impaired. This is demonstrated by reduced levels of productively infected cells in lymphoid organs and lower plasma viremia. Therefore, FoxP3(+) Treg cells are productively infected and play an important role in acute HIV-1 infection in vivo. The DKO-hu HSC mouse will be a valuable model to study human Treg functions and their role in HIV-1 pathogenesis in vivo.     

Dysfunctional CD4+,CD25+ regulatory T cells in untreated active systemic lupus erythematosus secondary to interferon-alpha-producing antigen-presenting cells

OBJECTIVE: To explore whether there are extrinsic factors that impair the suppressive function of CD4+,CD25+ regulatory T cells in patients with untreated active systemic lupus erythematosus (SLE). METHODS: We studied 15 patients with untreated active SLE, 10 patients with SLE in remission, and 15 healthy control subjects. Percentages of CD4+,CD25+,FoxP3+ Treg cells and levels of forkhead box P3 (FoxP3) protein were analyzed by flow cytometry. Expression of messenger RNA (mRNA) for FoxP3 in purified Treg cell populations was assessed by real-time polymerase chain reaction analysis. Experiments examining Treg cell function in SLE were designed to distinguish primary from secondary T cell dysfunction. Levels of interferon-alpha (IFNalpha) in supernatants from the function assays were determined with an IFN-stimulated response element-luciferase reporter assay. RESULTS: The percentage of CD4+,CD25+, FoxP3+ cells in peripheral blood was significantly increased in SLE patients as compared with controls (mean +/- SEM 9.11 +/- 0.73% versus 4.78 +/- 0.43%; P < 0.0001). We found no difference in FoxP3 expression at either the mRNA or protein level in any CD4+,CD25+ T cell subset from SLE patients as compared with controls. Antigen-presenting cells (APCs) from SLE patients were responsible for decreased Treg cell activity and could also render dysfunctional Treg cells from healthy control subjects. CD4+,CD25+ Treg cells from SLE patients exhibited normal suppressive activity when cultured with APCs from healthy controls. A partial Treg cell blockade effect was induced by the high levels of IFNalpha derived from SLE patient APCs. CONCLUSION: We suggest that blockade of Treg cell-mediated suppression by IFNalpha-producing APCs in SLE patients may contribute to a pathogenic loss of peripheral tolerance in this disease.     

慢性HBV感染者外周血CXCR5~+CD4~+Tfh细胞的测定及其与FoxP3~+Treg细胞的相关性

目的:探讨慢性乙型肝炎病毒(hepatitis Bvirus,HBV)感染不同阶段患者外周血CD4+T淋巴细胞中CD4+CXCR5+Tfh细胞及CD4+CD25+FoxP3+Treg细胞的百分比及其意义.方法:应用流式细胞术检测15例慢性无症状HBV携带者(chronic asymptomatic HBV carriers,AsC)、42例慢性乙型肝炎(chronic hepatitisB,CHB)患者(HBeAg阳性25例、HBeAg阴性17例)、11例非活动性HBsAg携带者(inactive HBsAg carriers,InC)外周血CD4+CXCR5+Tfh细胞及CD4+CD25+FoxP3+Treg细胞占CD4+T淋巴细胞的百分比,并与15例健康对照(healthycontrol,HC)进行比较.结果:AsC、HBeAg(+)CHB、HBeAg(-)CHB组外周血CD4+CXCR5+Tfh细胞占CD4+T淋巴细胞的比例分别为17.66(15.34%-20.56%),21.95(19.60%-26.32%),22.33(17.58%-24.85%),显著高于HC组的13.67(9.80%-15.32%),差异具有统计学意义(P<0.001).与AsC及InC组的16.11(12.33%-19.73%)相比,HBeAg(+)、HBeAg(-)CHB组外周血CD4+CXCR5+Tfh细胞占CD4+T淋巴细胞的比例显著升高(P<0.05).此外,AsC组外周血CD4+CD25+FoxP3+Treg细胞占CD4+T淋巴细胞的比例为7.70(6.35%-9.13%),显著高于HC组的6.53(5.54%-7.35%),P<0.05.HBeAg(+)CHB组外周血CD4+T淋巴细胞中CD4+CD25+FoxP3+Treg细胞的频率为7.52(6.09%-8.49%),与AsC组相比呈降低的趋势.外周血CD4+CXCR5+Tfh细胞占CD4+T淋巴细胞的比例与HBVDNA载量呈负性相关(r=-0.275,P<0.05);而与血清ALT水平、HBsAg滴度无相关性.结论:CD4+CXCR5+Tfh细胞可能参与了慢性HBV感染所介导的免疫反应,外周血CD4+CD25+FoxP3+Treg细胞及CD4+CXCR5+Tfh细胞的消长可能与疾病的活动性相关.     

In vivo-activated CD103+CD4+ regulatory T cells ameliorate ongoing chronic graft-versus-host disease

CD103 (alphaEbeta7) has been shown to be an excellent marker for identifying in vivo-activated FoxP3(+)CD4(+) regulatory T (Treg) cells. It is unknown whether reinfusion of in vivo-activated donor-type CD103(+) Treg cells from recipient can ameliorate ongoing chronic graft-versus-host disease (GVHD). Here, we showed that, in a chronic GVHD model of DBA/2 (H-2(d)) donor to BALB/c (H-2(d)) recipient, donor-type CD103(+) Treg cells from recipients were much more potent than CD25(hi) natural Treg cells from donors in reversing clinical signs of GVHD and tissue damage. Furthermore, in contrast to CD25(hi) natural Treg cells, CD103(+) Treg cells expressed high levels of CCR5 but low levels of CD62L and directly migrated to GVHD target tissues. In addition, the CD103(+) Treg cells strongly suppressed donor CD4(+) T-cell proliferation; they also induced apoptosis of in vivo-activated CD4(+) T and B cells and significantly reduced pathogenic T and B cells in GVHD target tissues. These results indicate that CD103(+) Treg cells from chronic GVHD recipients are functional, and reinfusion of the CD103(+) Treg cells can shift the balance between Treg cells and pathogenic T cells in chronic GVHD recipients and ameliorate ongoing disease.     

CD147 (Basigin/Emmprin) identifies FoxP3+CD45RO+CTLA4+-activated human regulatory T cells

Human CD4(+)FoxP3(+) T cells are functionally and phenotypically heterogeneous providing plasticity to immune activation and regulation. To better understand the functional dynamics within this subset, we first used a combined strategy of subcellular fractionation and proteomics to describe differences at the protein level between highly purified human CD4(+)CD25(+) and CD4(+)CD25(-) T-cell populations. This identified a set of membrane proteins highly expressed on the cell surface of human regulatory T cells (Tregs), including CD71, CD95, CD147, and CD148. CD147 (Basigin or Emmprin) divided CD4(+)CD25(+) cells into distinct subsets. Furthermore, CD147, CD25, FoxP3, and in particular CTLA-4 expression correlated. Phenotypical and functional analyses suggested that CD147 marks the switch between resting (CD45RA(+)) and activated (CD45RO(+)) subsets within the FoxP3(+) T-cell population. Sorting of regulatory T cells into CD147(-) and CD147(+) populations demonstrated that CD147 identifies an activated and highly suppressive CD45RO(+) Treg subset. When analyzing CD4(+) T cells for their cytokine producing potential, CD147 levels grouped the FoxP3(+) subset into 3 categories with different ability to produce IL-2, TNF-α, IFN-γ, and IL-17. Together, this suggests that CD147 is a direct marker for activated Tregs within the CD4(+)FoxP3(+) subset and may provide means to manipulate cells important for immune homeostasis.     

老年脓毒症休克患者CD4+CD25+调节性T细胞的变化及对预后的影响

目的 探讨老年脓毒症休克患者CD4+CD25+调节性T淋巴细胞(CD4+CD25+Treg)的变化及对预后的影响.方法 选择老年脓毒症休克患者75例,采用流式细胞仪检测患者外周血第1、4天和第7～10天CD4+CD25+叉头转录基因P3(FoxP3)/CD4+比例和白细胞DR抗原(HLA-DR)表达.结果 老年脓毒症休克患者平均年龄(69.2±7.5)岁,28 d病死率为53.3%.(1)休克死亡组与生存组CD4+CD25+FoxP3/CD4+比较,第1天(1.76±0.31)对(1.68±0.24)%,第4天(1.94±0.32)%对(1.82±0.28)%,差异均无统计学意义(P＞0.05),第7～10天休克死亡组(2.65±0.28)%,明显高于存活组(1.79±0.27)%,差异有统计学意义(t=11.30,P＜0.01);(2)死亡组第4天和第7～10天HLA-DR表达持续低下,显著低于生存组(t=7.29,t=16.80,均P＜0.01),并分别与CD4+CD25+FoxP3/CD4+比例呈显著负相关(r=-0.39,P＜0.05;r=-0.58,P＜0.01);(3)多元Logistic回归分析显示,脓毒症休克患者第7～10天CD4+CD25+FoxP3/CD4+(OR=3.47,95%CI:1.33～10.0)和HLA-DR(OR=0.27,95%CI:0.14～0.73)是影响其死亡的独立危险因素.结论 老年脓毒症休克患者CD4+CD25+Treg持续上升,提示机体免疫功能抑制,脓毒症休克死亡的危险性增加.     

CD25+ regulatory T cells isolated from HIV-infected individuals suppress the cytolytic and nonlytic antiviral activity of HIV-specific CD8+ T cells in vitro

HIV infection is characterized by CD4(+) T cell depletion and progressive immune dysfunction; particularly impacted are HIV-specific T cell responses. An important component of immune-mediated control of HIV replication, killing of infected cells, appears to be impaired, in part due to poor cytolytic activity of HIV-specific cytotoxic T cells (CTL). In vitro, several functions of HIV-specific T cells, such as cytokine production, can be enhanced by the depletion of the immunosuppressive CD25(+) FoxP3(+) CD4(+) regulatory (Treg) cell subset. However, the effect of CD25(+) Treg cells on virus-specific cytolytic activity in the context of HIV or any human viral infection has not been investigated. The present study demonstrates that CD25(+) Treg cells isolated from the peripheral blood of HIV-infected subjects significantly suppress HIV Gag-specific cytolytic activity in vitro. In addition, CD25(+) Treg cells suppress effector function (coexpression of TNF-alpha and IFN-gamma) of HIV-specific CD8(+) T cells that proliferate in response to HIV antigen. Finally, the secretion of HIV-inhibitory CC-chemokines by HIV-specific and nonspecific CD8(+) T cells is significantly reduced in the presence of CD25(+) Treg cells. These data suggest that CD25(+) Treg-mediated suppression of the antiviral activity of HIV-specific CD8(+) T cells could impact the ability of HIV-infected individuals to control HIV replication in vivo.     

Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis

CD4+CD25high regulatory T cells (Tregs) play a critical role in self-tolerance, as seen in murine autoimmunity. Studies on Tregs in human autoimmunity have focused primarily on peripheral blood samples. A study targeting diseased tissue should identify direct relationships between Tregs and autoimmunity. Peripheral blood samples were collected from 91 patients with primary biliary cirrhosis (PBC), 28 immediate relatives, and 41 healthy controls, and Treg frequencies were determined as a percentage of CD4+CD25high T cells in CD4+TCR-alphabeta+ T cells. A tissue-targeted determination of frequency and distribution of FoxP3+ Tregs was also performed on 90 different liver tissue specimens exhibiting PBC (n = 52), chronic hepatitis C (CHC) (n = 30), and autoimmune hepatitis (AIH) (n = 8). Treg suppression studies were performed on 50 PBC patients and 27 controls. Patients with PBC demonstrated a relative reduction of Tregs compared with controls (P < .0002). Interestingly, a deficiency in CD4+CD25+ Tregs was also found in the daughters and sisters of PBC patients compared with controls (P < .0007). However, functional studies did not reveal a global PBC Treg defect. The level of FoxP3-expressing Tregs was markedly lower in affected PBC portal tracts compared with CHC and AIH (P < .001). In addition, the CD8+T cell/FoxP3+ Treg ratio was significantly higher in livers of late-stage PBC compared with those of CHC (P < .001) and early-stage AIH (P < .001). In conclusion, these data provide support for a genetic modulation of Treg frequency and illustrate the role Tregs play in the loss of tolerance in PBC.     

Host CD4+CD25+ T cells can expand and comprise a major component of the Treg compartment after experimental HCT

Reconstitution of the recipient lymphoid compartment following hematopoietic cell transplantation (HCT) is typically delayed. The present studies investigated the residual host CD4(+)CD25(+)Foxp3(+) (Treg) compartment after several conditioning regimens, including T cell-depleted and T cell-replete HCT and observed (1) a small number of recipient Treg cells survived aggressive conditioning; (2) the surviving, that is, residual Tregs underwent marked expansion; and (3) recipient CD4(+)FoxP3(+) cells composed the majority of the Treg compartment for several months post-syngeneic HCT. Notably, residual Tregs also dominated the compartment post-HCT with T cell-depleted (TCD) major histocompatibility complex-matched allogeneic bone marrow but not following T cell-replete transplantations. The residual Treg cell compartment was functionally competent as assessed by in vitro lymphoid suppression and in vivo autoimmune disease transfer assay. These observations support the notion that functional host Tregs initially occupy a niche in lymphopenic transplantation recipients, undergo significant expansion, and contribute to the compartment for an extended period before donor-derived CD4(+)FoxP3(+) T cells eventually compose the majority of the compartment. In total, the findings suggest that the presence of host Tregs may be important to consider regarding elicitation of immune (eg, antitumor, vaccine) responses in recipients during the early post-transplant period involving autologous and certain allogeneic HCT regimens.     

Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines

CD4(+)CD25(high)FoxP3(+) regulatory T (Treg) cells limit antigen-specific immune responses and are a cause of suppressed anticancer immunity. In preclinical and clinical studies, we assessed the immune consequences of FoxP3(+) Treg-cell depletion in patients with advanced malignancies. We demonstrated that a CD25(high) targeting immunotoxin (denileukin diftitox) depleted FoxP3(+) Treg cells, decreased Treg-cell function, and enhanced antigen-specific T-cell responses in vitro. We then attempted to enhance antitumor immune responses in patients with carcinoembryonic antigen (CEA)-expressing malignancies by Treg-cell depletion. In a pilot study (n = 15), denileukin diftitox, given as a single dose or repeated dosing, was followed by immunizations with dendritic cells modified with the fowlpox vector rF-CEA(6D)-TRICOM. By flow cytometric analysis, we report the first direct evidence that circulating CD4(+)CD25(high)FoxP3(+) Treg cells are depleted after multiple doses of denileukin diftitox. Earlier induction of, and overall greater exposure to, the T-cell response to CEA was observed in the multiple-dose group, but not the single-dose group. These results indicate the potential for combining Treg-cell depletion with anticancer vaccines to enhance tumor antigen-specific immune responses and the need to explore dose and schedule of Treg depletion strategies in optimizing vaccine efforts.     

HBeAg(+)与HBeAg(-)乙型肝炎病毒携带者外周血CD4~+CD25~+调节性T淋巴细胞比例的变化及意义

目的探讨HBeAg(+)与HBeAg(-)HBV携带者外周血中CD4+CD25+调节性T淋巴细胞(Treg)的变化及其意义。方法 HBeAg(+)与HBeAg(-)HBV携带者两组各50例患者,应用流式细胞仪测定外周血CD3+T淋巴细胞所占比例、CD4+和CD8+T淋巴细胞所占比例及其比值、CD4+CD25+Treg所占比例;以同期门诊健康体检者20例为健康对照组。结果与健康对照组相比,HBeAg(+)与HBeAg(-)HBV携带者,在外周血CD3+T淋巴细胞、CD4+与CD8+T淋巴细胞所占比例差异无统计学意义。CD4+与CD8+T淋巴细胞比值,在HBeAg(+)HBV携带者有升高趋势,但与HBeAg(-)HBV携带者和对照组比较差异无统计学意义。HBeAg(+)HBV携带者,CD4+CD25+Treg所占比例较对照组明显升高,而HBeAg(-)HBV携带者,CD4+CD25+Treg所占比例较对照组明显降低,差异均有统计学意义。结论尽管肝功能在正常范围,HBeAg(+)与HBeAg(-)HBV携带者外周血CD4+CD25+Treg比例不同,HBeAg(+)HBV携带者高于健康对照组,而HBeAg(-)HBV携带者低于健康对照组,提示HBeAg(+)与HBeAg(-)HBV携带者处于不同的免疫状态。     

FoxP3+ Regulatory T Cells in Peripheral Blood of Patients with Epithelial Ovarian Cancer

Background: Ovarian cancer is the fifth leading cause of death from malignancy in women. CD4 +CD25+FoxP3+ regulatory T (Treg) cells are a subset of T lymphocytes with great inhibitory impact on immune response. Objectives: To investigate the percentage of CD4 +CD25+FoxP3+ regulatory T cells in the peripheral blood of the Iranian patients with epithelial ovarian cancer compared to healthy women and to evaluate the correlation of the Treg cell percentage with clinicopathological characteristics including cancer stage and CA-125 serum level. Methods: Seventeen women with epithelial ovarian cancer and 20 healthy subjects were enrolled in the study. Peripheral blood mononuclear cells were stained at the surface, for CD4 and CD25 molecules, followed by fixation, permeabilization and intracellular staining for FoxP3 molecule. After processing and flowcytometry analysis, prevalence of Treg cells was determined as the percentages of CD25 +FoxP3+ cells among CD4+ lymphocytes. Results: Despite no difference in the percentage of total CD4+ lymphocytes, analysis indicated that Treg cell percentage was significantly higher in ovarian cancer patients than controls (5.7 ± 3.1% versus 2.8 ± 1.4%, p=0.002). A trend toward higher Treg cells was observed in higher stages of ovarian cancer (III+IV) in comparison to lower stages (I+II) (6.5 ± 3.2% vs. 4.44 ± 2.7%, p=0.2). Higher percentage of Treg cells was also observed in the patients with high CA125 (CA-125 >100 U/mL) in comparison to those with low CA-125 serum level (CA-125 ≤100 U/mL) although the difference was not significant (6.44 versus 4.18%, p=0.19). Conclusion: Increased frequency of Tregs in ovarian cancer might participate in immune suppression in these patients. The findings collectively suggest the likely impact of Treg cell–targeted immunotherapy in ovarian cancer.     

Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells

Rapamycin is an immunosuppressive compound that is currently used to prevent acute graft rejection in humans. In addition, rapamycin has been shown to allow operational tolerance in murine models. However, a direct effect of rapamycin on T regulatory (Tr) cells, which play a key role in induction and maintenance of peripheral tolerance, has not been demonstrated so far. Here, we provide new evidence that rapamycin selectively expands the murine naturally occurring CD4(+)CD25(+)FoxP3(+) Tr cells in vitro. These expanded Tr cells suppress proliferation of syngeneic T cells in vitro and prevent allograft rejection in vivo. Interestingly, rapamycin does not block activation-induced cell death and proliferation of CD4(+) T cells in vitro. Based on this new mode of action, rapamycin can be used to expand CD4(+)CD25(+)FoxP3(+) Tr cells for ex vivo cellular therapy in T-cell-mediated diseases.