CD8~ T细胞在CD4~ T细胞耗竭小鼠卡氏肺孢子虫肺炎的致病作用(英文)

[目的 ]验证参与卡氏肺孢子虫致病过程中 ,宿主炎性反应及其对肺功能的影响。 [方法 ]:将小鼠CD4 T细胞耗竭或将小鼠CD4 和CD8 T细胞都耗竭后 ,经气管接种卡氏肺孢子虫。观察在CD8 T细胞缺如或存在的情况下 ,小鼠呼吸机能的改变和肺炎的程度。 [结果 ]耗竭CD4 和CD8 T细胞后 ,小鼠虽发生PCP ,但呼吸频率无明显加快 ,肺组织损伤程度也较轻。相反 ,仅耗竭CD4 T细胞保留CD8 T细胞的小鼠的呼吸频率明显加快 ,肺内炎性细胞反应和肺组织损伤程度均较重。支气管肺泡灌洗液 (BALF)中的CD8 T细胞和嗜中性白细胞的数量明显增多。 [结论 ]PCP的致病过程中 ,宿主的炎性细胞反应对肺功能有直接损伤作用 ,其中CD8 T细胞似起主要作用。     

Interferon-gamma and interleukin-4 reciprocally regulate CD8 expression in CD8+ T cells

The CD8 co-receptor can modulate CD8⁺ T cell function through its contributions to T cell receptor (TCR) binding and signaling. Here we show that IFN-γ and IL-4 exert opposing effects on the expression of CD8α mRNA and surface CD8 protein during CD8⁺ T cell activation. IL-4 caused down-regulation of surface CD8 on ovalbumin (OVA)_257–264-specific TCR-transgenic OT-I CD8⁺ T cells activated with OVA_257–264-coated antigen presenting cells or polyclonal stimuli, and on wild type CD8⁺ T cells activated with polyclonal stimuli. This effect was enhanced in each case when the cells lacked a functional IFN-γ or IFN-γR gene. When WT or IFN-γ-deficient OT-I CD8⁺ T cells were analyzed 9 days after co-injection with control or IL-4-expressing OVA⁺ tumor cells into RAG-2^−/−γc^−/− mice, CD8 levels were highest on WT donor cells from mice that received the control tumor and lowest on IFN-γ-deficient donor cells from mice that received the IL-4-expressing tumor. The latter CD8^low cells displayed markedly impaired binding of OVA_257–264/MHC tetramers and peptide/MHC-dependent degranulation. The data reveal an unexpected role for IFN-γ in tuning the CD8 co-receptor during primary CD8⁺ T cell activation both in vitro and in vivo.     

CD4:CD8 ratio in children with perinatally acquired HIV‐1 infection

Objectives

In adults with horizontally acquired HIV infection, an inverted CD4:CD8 ratio is associated with persistent immune activation, size of HIV reservoir and predicts an increased risk of non‐AIDS‐defining adverse events. Normalization of this ratio with antiretroviral therapy (ART) is suboptimal in adults, despite viral suppression, and is less well described in paediatric populations. We investigated rates of CD4:CD8 ratio recovery in children with perinatally acquired HIV infection (PaHIV) on ART.

Methods

A cross‐sectional, retrospective analysis of routine clinical data in children with PaHIV (5–18 years old) attending a single UK centre was carried out.

Results

CD4:CD8 normalization was seen in 62% of children on suppressive ART. A negative correlation was found between current CD4:CD8 ratio and age at start of ART. Positive correlations were found between current CD4:CD8 ratio and total time with suppressed HIV viral load and nadir CD4 counts. Multiple linear regression analysis showed that age at start of ART was significantly associated with current CD4:CD8 ratio (standardized β = ?0.680; P < 0.001). Patient sex, ethnicity and antiretroviral regimen did not affect ratio recovery.

Conclusions

We found higher rates of CD4:CD8 ratio normalization compared with previous adult studies. Children who started ART at a younger age were more likely to recover a normal ratio. The current policy of universal treatment for all HIV‐positive adults and children will enhance immunological normalization.

     

CD8~+ T细胞在CD4~+ T细胞耗竭小鼠卡氏肺孢子虫肺炎的致病作用

[目的 ]验证参与卡氏肺孢子虫致病过程中 ,宿主炎性反应及其对肺功能的影响。 [方法 ]:将小鼠CD4+ T细胞耗竭或将小鼠CD4+ 和CD8+ T细胞都耗竭后 ,经气管接种卡氏肺孢子虫。观察在CD8+ T细胞缺如或存在的情况下 ,小鼠呼吸机能的改变和肺炎的程度。 [结果 ]耗竭CD4+ 和CD8+ T细胞后 ,小鼠虽发生PCP ,但呼吸频率无明显加快 ,肺组织损伤程度也较轻。相反 ,仅耗竭CD4+ T细胞保留CD8+ T细胞的小鼠的呼吸频率明显加快 ,肺内炎性细胞反应和肺组织损伤程度均较重。支气管肺泡灌洗液 (BALF)中的CD8+ T细胞和嗜中性白细胞的数量明显增多。 [结论 ]PCP的致病过程中 ,宿主的炎性细胞反应对肺功能有直接损伤作用 ,其中CD8+ T细胞似起主要作用。     

Demonstration of strain-specific CD8 T cell responses to Theileria annulata

The present study set out to examine the nature and specificity of the bovine CD8 T cell response at the clonal level in a group of eight animals immunized with a cloned population of Theileria annulata . The results demonstrated that immunized animals generated parasite-specific CD8 T cells that produced IFNγ in response to parasite stimulation but had highly variable levels of cytotoxicity for parasitized cells. The study also demonstrated that these parasite-specific CD8 T cells could be propagated and cloned in vitro from the memory T cell pool of cattle immunized with live T. annulata parasites. Within the small group of animals studied, there was evidence that responses were preferentially directed to antigens presented by an A10⁺ class I major histocompatibility complex (MHC) haplotype, suggesting that responses restricted by products of this haplotype may be dominant. The A10-restricted responses showed differential recognition of different parasite isolates and clones. By using a cloned population of parasites both for immunization of the animals and for in vitro analyses of the responses, we obtained unambiguous evidence that at least a proportion of CD8 T cells restricted by one MHC haplotype were parasite strain restricted.     

CD8 and CD4 T Cells in West Nile Virus Immunity and Pathogenesis

CD4 and CD8 T lymphocytes are adaptive immune cells that play a key role in the immune response to pathogens. They have been extensively studied in a variety of model systems and the mechanisms by which they function are well described. However, the responses by these cell types vary widely from pathogen to pathogen. In this review, we will discuss the role of CD8 and CD4 T cells in the immune response to West Nile virus infection.     

肺结核患者CD4、CD8淋巴细胞变化分析

目的　观察肺结核患者CD4、CD8淋巴细胞变化,探讨其免疫状态的改变及其意义。方法 用流式细胞仪测定31例成人肺结核及12例对照组的CD4、CD8计数值,对测定结果进行统计学分析。结果 病人组CD4值明显下降,CD8值无明显变化,CD4下降幅度与病情严重程度、排菌状态无明显关联。结论 成人肺结核患者存在以CD4T淋巴细胞下降为突出表现的细胞免疫受损,但其对病情发生、发展无独立的影响作用。     

阻塞性睡眠呼吸暂停低通气综合征患者CD4+及CD8+细胞的活化

目的探讨CD4 及CD8 细胞在阻塞性睡眠呼吸暂停低通气综合征(OSAHS)发病中的作用。方法研究对象均进行多导睡眠监测(PSG),随机抽取研究对象,分为正常对照组、轻度OSAHS组、中度OSAHS组和重度OSAHS组各29例,16例重度OSAHS患者同时进行nCPAP治疗1月。流式细胞仪测定CD4 和CD8 细胞分别占总T细胞的百分比,活化的CD4 及CD8 细胞分别占全部CD4 和CD8 细胞的百分比。结果①正常对照组、轻度、中度及重度OSAHS患者,CD4 占总T细胞的百分比分别为71.0%±8.0%、65.0%±4.5%、54.2%±6.8%及43.0%±4.7%;CD8 占总T细胞的百分比分别为24.4%±8.7%、30.3%±5.0%、40.4%±7.0%和49.4%±6.7%。CD4 细胞的活化率分别为4.4%±0.5%、5.0%±0.6%、8.1%±0.5%和9.7%±0.7%;CD8 细胞的活化率分别为7.5%±0.7%、8.2%±0.5%、12.0%±1.1%和13.3%±1.1%。两两对比差异有显著性,P均<0.001。重度OHAHS患者nCPAP治疗后,CD4 细胞占总T细胞的比例明显上升;而CD8 细胞占总T细胞的比例则明显下降。CD4 及CD8 细胞的活化率均明显下降。两两对比差异有显著性,P均<0.05。②Spearman等级相关分析表明,OSAHS的严重程度与CD4 细胞百分比呈负相关,与CD8 细胞、活化的CD4 及CD8 细胞百分比呈正相关(rs分别为-0.5432、0.5166、0.4315、0.4761)。结论OSAHS患者可能存在细胞免疫功能的下降,T细胞包括CD4 细胞及CD8 细胞有异常活化,且病情加重以上变化更明显,nCPAP可逆转这种改变。     

Prevention of CD8 T Cell Deletion during Chronic Viral Infection

During chronic viral infections, CD8 T cells rapidly lose antiviral and immune-stimulatory functions in a sustained program termed exhaustion. In addition to this loss of function, CD8 T cells with the highest affinity for viral antigen can be physically deleted. Consequently, treatments designed to restore function to exhausted cells and control chronic viral replication are limited from the onset by the decreased breadth of the antiviral T cell response. Yet, it remains unclear why certain populations of CD8 T cells are deleted while others are preserved in an exhausted state. We report that CD8 T cell deletion during chronic viral infection can be prevented by therapeutically lowering viral replication early after infection. The initial resistance to deletion enabled long-term maintenance of antiviral cytolytic activity of the otherwise deleted high-affinity CD8 T cells. In combination with decreased virus titers, CD4 T cell help and prolonged interactions with costimulatory molecules B7-1/B7-2 were required to prevent CD8 T cell deletion. Thus, therapeutic strategies to decrease early virus replication could enhance virus-specific CD8 T cell diversity and function during chronic infection.     

雷公藤内酯醇对EAE大鼠外周血CD4+、CD8+的影响

目的探讨雷公藤内酯醇（Tri）对急性实验性变态反应性脑脊髓炎（EAE）大鼠外周血CD4^＋、CD8^＋的影响。方法模型组采用豚鼠髓鞘蛋白和福氏完全佐剂诱发大鼠EAE;治疗组在模型组的基础上予以不同剂量Tri,观察各组的发病情况;流式细胞仪检测外周血CD4^＋、CD8^＋;HE染色和Loyez氏髓鞘染色分别观察病理和髓鞘改变。结果高剂量Tri组未出现临床症状,与模型组和低剂量Tri组比较,高剂量Tri组CD8^＋明显增高、CD4^＋／CD8^＋值明显降低（P〈0．05,〈0．05）;脑和脊髓炎症细胞浸润明显减少;髓鞘结构完整。结论Tri对EAE的治疗有剂量相关性,其作用机制与其增加CD8^＋、降低CD4^＋／CD8^＋值,从而调节机体免疫平衡有关。     

健康傣族人CD3+ CD4+和CD8+ T淋巴细胞绝对数正常值调查

目的了解德宏州健康傣族人群外周静脉血CD3 、CD4 、CD8 T淋巴细胞绝对数和CD4 /CD8 比值的正常值范围。方法应用流式细胞仪(FACSCount)检测253例健康傣族人的CD3 、CD4 、CD8 T淋巴细胞绝对数和CD4 /CD8 比值,并观察以上数值在性别和年龄上的差异。结果CD3 、CD4 、CD8 和CD4 /CD8 的正常值参考范围分别为(1 543±443)个/μl(、849±261)个/μl(、567±225)个/μl和1.63±0.55。CD3 、CD4 在性别和年龄组别间的差异均无统计学意义,而CD8 和CD4 /CD8 在年龄组别间的差异有统计学意义。结论初步建立了健康傣族人群CD3 、CD4 、CD8 和CD4 /CD8 的正常值参考范围,对于指导德宏州艾滋病的诊断及治疗工作有重要意义。     

Decreased numbers of signal-joint T cell receptor excision circle-containing CD4+ and CD8+ cells in systemic lupus erythematosus patients

Systemic lupus erythematosus (SLE) patients have a decreased number of peripheral blood T cells containing signal-joint T cell receptor excision circles (Sj TRECs), which are considered an indicator of thymic output. The objective of this study was to investigate the mechanism of the decrease in such T cells. Peripheral blood T cells from SLE patients were classified into CD4+ and CD8+ cells. Sj TREC levels were measured by real-time PCR. Telomerase activity was determined by the telomeric repeat amplification protocol assay. The numbers of Sj TREC containing CD4+ and CD8+ cells were lower in the peripheral blood of SLE patients than in the controls. A correlation was found between the numbers of Sj TREC-positive CD4+ and CD8+ cells. The level of TRECs is influenced by an increase in cell division. To examine this increase, telomerase activity as an indicator of cell division was measured simultaneously; however, there was no correlation between the Sj TREC level and telomerase activity. These results suggest that decreased thymic output occurs in SLE patients.     

Correlation between CD4/CD8 ratio and neurocognitive performance during early HIV infection

Introduction

CD4/CD8 ratio is a marker of immune activation in HIV infection and has been associated with neurocognitive performance during chronic infection, but little is known about the early phases. The aim of this study was to examine the relationship between blood CD4/CD8 ratio and central nervous system endpoints in primary HIV infection (PHI) before and after antiretroviral treatment (ART).

Methods

This was a retrospective analysis of the Primary Infection Stage CNS Events Study (PISCES) cohort. We longitudinally assessed blood and cerebrospinal fluid (CSF) markers of inflammation, immune activation and neuronal injury, and neuropsychological testing performance (NPZ4, an average of three motor and one processing speed tests, and a summarized total score, NPZ11, including also executive function, learning and memory) in ART-naïve participants enrolled during PHI. Spearman correlation and linear mixed models assessed the relationships between the trajectory of CD4/CD8 ratio over time and neurocognitive performance, blood and CSF markers of immune activation and neuronal injury.

Results

In all, 109 PHI participants were enrolled. The mean CD4/CD8 ratio decreased with longer time from infection to starting treatment (p < 0.001). Every unit increase in NPZ4 score was independently associated with a 0.15 increase in CD4/CD8 ratio (95% CI: 0.002–0.29; p = 0.047), whereas no correlation was found between CD4/CD8 ratio and NPZ11. Among the cognitive domains, only a change in processing speed was correlated with CD4/CD8 ratio over time (p = 0.03). The trajectory of the CD4/CD8 ratio was negatively correlated with change in CSF neurofilament light chain (p = 0.04).

Conclusions

The trajectory of CD4/CD8 ratio was independently associated with motor/psychomotor speed performance, suggesting that immune activation is involved in brain injury during the early stages of the infection.     

CD4CD4+和CD8CD4+ T淋巴细胞与动脉粥样硬化相关性研究进展

在动脉粥样硬化的发生发展过程中CD4+和CD8+T淋巴细胞有着重要的意义,近年来越来越多的研究显示了CD4+和CD8+T淋巴细胞参与了动脉粥样硬化的免疫炎症反应,受到了国内外学者的关注,同时,也成为心血管领域和免疫学界难以攻关的课题。本文对CD4+和CD8+T淋巴细胞与动脉粥样硬化相关性研究进展做一简要综述。     

肺结核患者外周血CD_4~+、CD_8~+T细胞Blimp-1表达下降

目的研究活动性肺结核患者外周血单个核细胞(PBMCs)Blimp-1的表达及临床意义。方法采集31例活动期肺结核患者和45位健康对照组外周血,纯化PBMCs,用结核分枝杆菌ESAT-6和CFP-10混合性抗原肽库刺激,通过细胞表面标记和细胞内细胞因子染色技术,采用流式技术检测CD+4、CD+8T细胞Blimp-1的表达。结果与对照组比较,肺结核患者PBMCs中的CD+4、CD+8T细胞亚群分布出现显著性下降,且肺结核患者CD+4T细胞中Blimp-1的表达比例(%)下降(肺结核组89.5%(83.8%,95.7%),对照组94.5%(89.8%,98.7%),P0.05),且CD+4、CD+8T细胞中Blimp-1的表达量(平均荧光强度)也显著性下降(CD+4T细胞:肺结核组9.28(7.5,18.9),对照组15.4(11,25.4),P0.05);CD+8T细胞:肺结核组9.01(6.08,14.7),对照组14.2(9.53,23.1),P0.05)。结论活动期肺结核CD+4、CD+8T细胞群内Blimp-1的表达下降可能会使效应性和调节性T细胞的分化出现异常。Blimp-1可能参与结核病的疾病进程,这为研究结核病的诊断和治疗提供了线索。     

IL-15 as a mediator of CD4+ help for CD8+ T cell longevity and avoidance of TRAIL-mediated apoptosis

CD4+ helper T cells contribute to the induction and maintenance of antigen-specific CD8+ T cells. Their absence results in short-lived antigen-specific CD8+ T cells and defective secondary CD8+ T cell responses because of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Here, we show that IL-15 codelivered with vaccines can overcome CD4+ T cell deficiency for promoting longevity of antigen-specific CD8+ T cells and avoidance of TRAIL-mediated apoptosis. In both priming and secondary responses, IL-15 down-regulates proapoptotic Bax, an intermediate in TRAIL-mediated apoptosis, and increases anti-apoptotic Bcl-X(L) in CD8+ T cells. Thus, IL-15 is sufficient to mimic CD4+ T cell help. Antigen-specific CD4+ T cells induce dendritic cells (DCs) to produce IL-15. IL-15 is also necessary for optimal help, because helper cells do not deliver effective help through IL-15-/- DCs. Therefore, IL-15 codelivered with vaccines can overcome CD4+ helper T cell deficiency for induction of functionally efficient CD8+ T cells and maintenance of CD8+ cytotoxic T lymphocytes (CTLs), and IL-15 is probably one of the natural mediators of help. These findings suggest new vaccine strategies against infections and cancers, especially in individuals with CD4-deficiency.     

Decrease in CD4+CD25+ and CD8+CD28+ T cells in interstitial pneumonitis associated with rheumatic disease

Abstract

The expression of CD25 or CD28 on T cells was examined in patients with rheumatic diseases associated with interstitial pneumonitis (IP), in order to investigate the conditions of CD4⁺CD25⁺ regulatory T cells and CD8⁺CD28^? suppressor T cells. Fifty-five patients with various rheumatic diseases and 23 normal controls were enrolled. CD4⁺CD25⁺ T cells of patients with IP were significantly decreased in comparison with non-IP patients, and the ratio of CD8⁺CD28^? T cells in patients with IP was significantly higher than that in non-IP patients or normal controls. These results for CD8⁺CD28^? T cells were in accord with the decrease in CD8⁺CD28⁺ T cells, and may be related to activation-induced CD8⁺CD28⁺ T-cell death. Thus, the abnormality of CD4⁺CD25⁺ regulatory T cells may be related to the pathogenesis of IP, and the survival and activation of CD8⁺ T cells.     

Inhibition of Plasmodium falciparum growth in vitro by CD4+ and CD8+ T cells from non-exposed donors

T cells from most adult non-exposed donors, which express a memory phenotype (CD45RO+), can respond by proliferation to P. falciparum asexual stages in vitro. Such cells may have arisen from exposure to environmental organisms. To address the efficacy of such cells in eliminating parasites and investigate the mechanisms involved, we have used an in vitro assay where parasite growth can be precisely monitored in the presence of different cell preparations. Unfractionated peripheral blood mononuclear cells (PBMC) from both malaria-exposed and non-exposed donors inhibited parasite growth by up to 62% in a two day assay. Purified T cells in the presence of adherent cells had a similar effect, but purified T cells alone or adherent cells alone had minimal effect. Antigens released at the time of schizont rupture were maximally effective in stimulating interferon-γ (IFNγ) production. Neutralizing antibodies to IFNγ showed a partial reduction of growth inhibition in some individuals tested suggesting that different mechanisms may be operative. Neutralizing antibody to TNFα had a partial effect in combination with anti-IFNγ. Antibodies to IL-1 and IL-4 had no effect. T cell fractionation experiments showed that while purified CD4⁺ T cells from some donors produced IFNγ and inhibited parasite growth, purified CD8⁺ T cells could inhibit parasite growth to a greater extent without production of detectable IFNγ. Four parasitised red blood cell clones (CD4⁺, TCRαβ⁺, IFNγ producing) derived from non-exposed donors inhibited parasite growth to comparable levels, but one clone showed low production of IFNγ whilst the other three produced high levels. Our data show that T cells from non-exposed donors have the potential to eliminate malaria parasites via non-IFNγ dependent mechanisms. Such mechanisms may contribute to a degree of innate resistance to malaria in vivo, and may be able to be targeted by malaria vaccine programs.