Origin of CD8^＋ Effector and Memory T Cell Subsets

It is well accepted that CD8＋ T cells play a pivotal role in providing protection against infection with intracellular pathogens and some tumors. In many cases protective immunity is maintained for long periods of time （immunological memory）. Over the past years, it has become evident that in order to fulfill these multiple tasks, distinct subsets of effector and memory T cells have to be generated. Until today, however, little is known about the underlying mechanisms of subset differentiation and the timing of lineage fate decisions. In this context, it is of special importance to determine at which level of clonal expansion functional and phenotypical heterogeneity is achieved. Different models for T cell subset diversification have been proposed; these differ mainly in the time point during priming and clonal expansion （prior, during, or beyond the first cell division） when differentiation programs are induced. Recently developed single-cell adoptive transfer technology has allowed us to demonstrate that individual precursor cell still bears the full plasticity to develop into a plethora different T cell subsets. This observation targets the shaping of T cell subset differentiation towards factors that are still operative beyond the first cell division. These findings have important implications for vaccine development, as the modulation of differentiation patterns towards distinct subsets could become a powerful strategy to enhance the efficacy and quality of vaccines. Cellular ＆ Molecular Immunology.     

献血员CD8^＋T细胞的增另对CD4^＋T细胞的抑制作用

实验发现６５％体检合格的献血员外周血ＣＤ８＾＋Ｔ细胞数量明显增加,并伴随ＣＤ１６＾＋淋巴细胞数量的增加。这些异常的淋巴细胞与葡萄球菌肠毒素Ｂ（ＳＥＢ）共同２６ｄ,ＣＤ４＾＋Ｔ细胞无增殖反应。预先用抗ＣＤ８抗体去除ＣＤ８＾＋Ｔ细胞（去除率〉９０％）再用ＳＥＢ刺激淋巴细胞,其应答能力恢复正常,增殖的细胞是ＣＤ４＾＋Ｔ细胞,它们由３４．０４％增加到９９．３４％。ＣＤ８＾＋Ｔ细胞由最初的９．５７％降低到０     

CD8^＋T细胞的调节性特性

摘要随着免疫学，内科学及移植学的发展，CD8^ T细胞日益受到重视。它不仅是细胞毒性效应T细胞，而且也是具有免疫抑制作用的调节性T细胞。CD8^ 调节性T细胞在生理条件下对机体自身稳态的维持，以及在器官移植，自身免疫性疾病及病毒感染和肿瘤等病理状态下都起着较为重要的作用。     

分泌细胞因子的CD8^＋T细胞亚群研究进展

Ｔ细胞具有功能不同的亚群，其中ＣＤ４＾＋辅助Ｔ细胞（ＴＨ）的亚群分类及功能早已成定论。近几年的研究发现传统的ＣＤ８＾＋细胞毒Ｔ细胞（ＣＴＬ）也可分泌与ＣＤ４＾＋Ｔ细胞相似的细胞因子，也可分为两类亚群，分别定义为Ｔｃ１和Ｔｃ２。本文就近年来这方面的研究进展作一综述。     

CD8^＋T淋巴细胞非细胞毒性抗HIV作用研究进展

细胞免疫在抗病毒感染中发挥着至关重要的作用。人类免疫缺陷病毒(HIV)感染所引起的细胞免疫反应是由CD8^ T淋巴细胞的亚群细胞毒性T细胞(CTL)介导的先天免疫。CIIs一方面通过细胞毒性作用杀伤感染的细胞，另一方面分泌可溶性抗病毒因子(CAF)发挥直接的抗病毒作用，因此成为HIV感染中细胞免疫的重要组成部分。本就HIV感染这一疾病过程中CD8^ T淋巴细胞所发挥的非细胞毒性抗病毒效应作一概述。     

健康双生子外周血CD4^＋和CD8^＋ T细胞亚群相对计数遗传度研究

目的分析围生期及生命早期环境因素与外周血CD4＋、CD8＋T细胞相对计数的关系,估计CD4＋和CD8＋T细胞亚群的遗传度。方法采用双生子研究设计,经纳入与排除标准选取在新疆医科大学第一附属医院、乌鲁木齐市妇幼保健医院、新疆维吾尔自治区人民医院、中国人民解放军乌鲁木齐总医院和乌鲁木齐市第一人民医院出生的健康双生子。收集研究对象一般家庭状况、母亲孕期及分娩状况、出生时状况等信息,在双生子满1周岁时进行体检。体重和身高等体格发育指标依照＂1995年中国九市7岁以下儿童体格发育调查研究＂标准进行测量。测定外周血CD4＋和CD8＋T细胞亚群相对计数,并通过微卫星DNA基因分型技术进行卵型鉴定。CD4＋和CD8＋T细胞亚群的遗传度估计应用Mx软件进行分析。结果研究期间共有172对双生子进入分析,其中82对为（47.7%）同卵双生子（MZ）,90对为异卵双生子（DZ）。Apgar评分与MZ、DZ组CD4＋T细胞相对计数呈弱正相关（rMZ=0.16,rDZ=0.14,P〈0.05）。最终选择AE模型得到1岁幼儿外周血CD4＋和CD8＋T细胞的遗传度分别为61.8%（95%CI：38.3%-74.8%）与57.3%（95%CI：34.5%-70.2%）。结论 1岁幼儿外周血CD4＋和CD8＋T细胞亚群遗传度高于成人水平,Apgar评分或与CD4＋和CD8＋T细胞亚群相对计数相关。     

Defect of CD8^＋ Memory T Cells Developed in Absence of IL-12 Priming for Secondary Expansion

IL-12 priming plays an important role in stimulation of CD8^＋ effector T cells and development of CD8^＋ memory T （Tm） cells. However, the functional alteration of CD8^＋ Tm cells developed in the absence of IL-12 priming is elusive. In this study, we investigated the capacity of secondary expansion of CD8~ Tm cells developed from transgenic OT I CD8^＋ T cells. The latter cells were in vitro and in vivo stimulated by ovalbumin （OVA）-pulsed dendritic cells [DCovA and （IL-12^-/-）DCovA] derived from wild-type C57BL/6 and IL-12 gene knockout mice, respectively. We demonstrated that IL-12 priming is important not only in CD8^＋ T cell clonal expansion, but also in generation of CD8^＋ Tm cells with the capacity of secondary expansion upon antigen re-encounter. However, IL-12 signaling is not involved in CD8^＋ Tm cell survival and recall responses. Therefore, this study provides useful information for vaccine design and development. Cellular ＆ Molecular Immunology.     

记忆性CD8^＋T淋巴细胞维持的细胞与分子基础

记忆性CD8^ T细胞在抗病毒，抗胞内菌感染及抗肿瘤等方面发挥重要作用，其维持不需要B细胞，CD4^ T细胞及抗原的存在；MHC份子，IL-15，IFN-I、IL-2等在维持中起重要的作用。CD8^ T记忆细胞长期存在的基因机制仍不详。     

The Qa-1 Dependent CD8^＋ T Cell Mediated Regulatory Pathway

The immune system has evolved a variety of regulatory mechanisms to ensure the peripheral self-tolerance as well as the optimal capacity to elicit effective anti-infection immunity. At present, there is no satisfactory conceptual framework to explain how the peripheral immunity is regulated at a biological system level, which enables the immune system to perform its essential functions to mount effective immunity to virtually any foreign antigens but avoid harmful immune responses to self. In this regard, during the past few years, an “affinity/avidity model of peripheral T cell regulation” has been proposed and tested, which opens up a new paradigm to understand how the peripheral immunity, to both self and foreign antigens, is regulated. The paradigm is based on the discovery of a subset CD8^＋ T cells with TCRs which specifically recognize a unique set of self-peptides presented by the MHC class Ib molecule Qa-I differentially expressed on T cells as a function of the affinity/avidity of T cell activation. These Qa-1 restricted CD8^＋ T cells represent an example of how the immune system utilizes a unified mechanism to regulate adaptive immunity to both self and foreign antigens. Thus, by selectively down-regulating T cells of intermediate affinity/avidity, to any antigens, the immune system controls the adaptive immunity without the necessity to distinguish self from non-self in the periphery at the level of T cell regulation. Cellular ＆ Molecular Immunology. 2005;2（3）：161-167.     

非细胞毒性CD8^＋T细胞应答—控制HIV感染的有效途径

以往一直认为，ＨＩＶ感染者体内的细胞免疫主要是由细胞毒性ＣＤ８＾＋Ｔ细胞介导，导致病毒感染细胞ＣＤ４＾＋细胞的裂解或凋亡。但近年来发现，非细胞毒性ＣＤ８＾＋Ｔ细腻可在不杀伤感染细胞的情况下有效控制ＨＩＶ的感染。     

尖锐湿疣患者皮损及外周血CD4^＋和CD8^＋细胞免疫功能的检测

目的通过对尖锐湿疣（CA）患者皮损及外周血CD4^＋和CD8^＋细胞免疫功能检测的分析,探讨尖锐湿疣患者细胞免疫功能的变化及其对CA的影响。方法通过流式细胞仪（FCM）对40例CA患者及20名正常人外周血进行反映细胞免疫功能的T淋巴细胞亚群的检测,实验采用免疫组化的方法对40例CA皮损样本中CD4^＋和CD8^＋细胞的数目进行检测。结果CA患者外周血及皮损较正常对照组中的CD8^＋细胞百分率增加．CD4^＋细胞百分率及CD4^＋／CD8^＋比值降低。结论CA患者存在全身和局部的细胞免疫功能低下,而且局部皮损细胞免疫功能低下可能在CA的发病中具有重要作用。     

手足口病患儿T淋巴细胞亚群与CD3^＋CD4ˉCD8ˉ双阴性调节性T细胞的检测及其临床意义

目的探讨外周血T淋巴细胞亚群及CD3^＋CD4ˉCD8ˉ双阴性调节性T细胞在手足口病病人发病中的临床意义。方法采用流式细胞术检测了46例手足口病患者以及17例健康体检者外周血T细胞亚群CD3^＋、CD3^＋CD4ˉCD8^＋、CD3^＋CD4^＋CD8^＋、CD3^＋CD4^＋CD8ˉ与CD3^＋CD4ˉCD8ˉ双阴性调节性T细胞水平。结果与正常对照组相比,手足口病患者组CD3^＋、CD3^＋CD4ˉCD8’、CD3^＋CD4ˉCD8ˉ双阴性调节性T细胞的百分率降低（P值分别为0．008、0．050、0．025）。CD3^＋CD4^＋CD8^＋、CD3^＋CD4^＋CD8ˉ百分率以及CD4／CD8比值差异无统计学意义（P值分别为0．847、0．775、0．149）,以上各细胞亚群的百分率以及CD4／CD8比值在年龄与性别方面差异无统计学意义。结论手足口病患者CD3^＋CD4ˉCD8ˉ双阴性调节性T细胞、CD3^＋、CD3^＋CD4ˉCD8^＋异常变化提示其免疫功能异常。     

A naturally occurring CD8^＋CD122^＋ T-cell subset as a memory-like Treg family

Despite extensive studies on CD4^＋CD25^＋ regulatory T cells （Tregs） during the past decade, the progress on their clinical translation remains stagnant. Mounting evidence suggests that naturally occurring CD8^＋CD122^＋ T cells are also Tregs with the capacity to inhibit T-cell responses and suppress autoimmunity as well as alloimmunity. In fact, they are memory-like Tregs that resemble a central memory T cell （TcM） phenotype. The mechanisms underlying their suppression are still not well understood, although they may include IL-IO production. We have recently demonstrated that programmed death-1 （PD-1） expression distinguishes between regulatory and memory CD8^＋CD122^＋ T cells and that CD8^＋CD122^＋ Tregs undergo faster homeostatic proliferation and are more potent in the suppression of allograft rejection than conventional CD4^＋CD25^＋ Tregs. These findings may open a new line of investigation for accelerating effective Treg therapies in the clinic. In this review, we summarize the significant progress in this promising field of CD8^＋CD122^＋ Treg research and discuss their phenotypes, suppressive roles in autoimmunity and alloimmunity, functional requirements, mechanisms of action and potential applications in the clinic.     

RA患者外周血CD8＋CD28-和CD4＋CD25＋调节性T细胞的表达及疾病活动性指标相关性分析

目的：检测类风湿性关节炎（RA）患者外周血CD8＋CD28-、CD4＋CD25＋调节性T细胞亚群,探讨其与临床活动性指标的关系。方法：采用流式细胞术检测台州医院RA患者外周血CD8＋CD28-、CD4＋CD25＋ T细胞亚群比例,探讨调节性T细胞与RA活动性、类风湿因子（RF）、免疫球蛋白（Ig）、C反应蛋白（CRP）、补体C3、抗CCP抗体、抗核抗体（ANA）、血小板（PLT）及血沉（ESR）的关系。结果：活动期RA患者外周血CD4＋CD25＋调节性T细胞亚群比例显著低于正常对照组（P〈0.01）,但稳定期RA患者与正常对照组结果差异无统计学意义（P〉0.05）。活动期和稳定期RA患者CD8＋CD28-与正常对照组相比较,结果无统计学意义（P〉0.05）;CD4＋CD25＋与CRP密切相关（r=-0.593,P〈0.05）,CD8＋CD28-与ESR相关系数呈弱相关。CD4＋CD25＋和CD8＋CD28-细胞与RF、IGG、C3、ANA、anti-CCP和PLT未见明显相关性。结论：活动期RA患者外周血CD4＋CD25＋ T细胞亚群比例减少,CD4＋CD25＋ T细胞可能与类风湿性关节炎疾病进展有关。     

慢性乙型肝炎患者外周血CD8^＋ T细胞的KIR3DL1表达的探讨

目的：检测慢性乙型肝炎患者外周血CD8＋T细胞的KIR3DL1表达情况。方法：：采用流式细胞术检测慢性乙型肝炎患者外周血CD8＋T细胞的KIR3DL1分子表达,并与正常对照组比较。结果：慢性乙型肝炎患者外周血CD8＋T细胞的KIR3DL1分子表达明显高于对照组。结论：慢性乙型肝炎患者CD8＋T细胞的KIR3DL1表达显著增加。     

EBV-Induced Human CD8^＋ NKT Cells Synergise CD4^＋ NKT Cells Suppressing EBV-Associated Tumours upon Induction of Thl-Bias

CD8^＋ natural killer T （NKT） cells from EBV-associated tumour patients are quantitatively and functionally impaired. EBV-induced CD8^＋ NKT cells drive syngeneic T cells into a Thl-bias response to suppress EBV-associated malignancies. IL-4-biased CD4^＋ NKT cells do not affect either syngeneic T cell cytotoxicity or Th cytokine secretion. Circulating mDC1 cells from patients with EBV-associated malignancies impair the production of IFN-T by CD8^＋ NKT cells. In this study, we have established a human-thymus-SCID chimaera model to further investigate the underlying mechanism of EBV-induced CD8^＋ NKT cells in suppressing EBV-associated malignancies. In the human-thymus-SCID chimera, EBV-induced CD8^＋ NKT cells suppress EBV-associated malignancies in a manner dependent on the Thl-bias response and syngeneic CD3^＋ T cells. However, adoptive transfer with CD4^＋ NKT cells alone inhibits T cell immunity. Interestingly, CD4^＋ NKT cells themselves secrete high levels of IL-2, enhancing the persistence of adoptively transferred CD8^＋ NKT cells and T cells, thereby leading to a more pronounced T cell anti-tumour response in chimaeras co-transferred with CD4^＋ and CD8^＋ NKT cells. Thus, immune reconstitution with EBV-induced CD4^＋ and CD8^＋ NKT cells synergistically enhances T cell tumour immunity, providing a potential prophylactic and therapeutic treatment for EBV-associated malignancies.     

Global Gene Expression Profiling in Interleukin-12-Induced Activation of CD8^＋ Cytotoxic T Lymphocytes against MouseMammary Carcinoma

Interleukin-12(IL-12) is a critical cytokine representing the link between the cellular and humoral branches ofhost immune defense apparatus.IL-12-induced cytotoxic lymphocyte(CTL) development is a centralmechanism in immune responses against intracellular infectious agents as well as malignant growth.However,the molecular basis of tumor-specific CTL responses mediated by IL-12 remains poorly defined.In this study,we addressed this issue in a comprehensive manner to probe into IL-12-induced anti-tumor responses by globalgene expression profiling of mRNA expression in CD8~+ T cells in a transplantable syngeneic mouse mammarycarcinoma model treated or not with recombinant IL-12.A strong tumor regression was induced by the IL-12treatment.An introspection of differential gene expression at an early stage of the IL-12-initiated CTLactivation reveals interesting genes and molecular pathways that may account for the marked tumor regression,and is likely to provide a rich source of potential targets for further research and development of effectivetherapeutic modalities.Cellular & Molecular Immunology.2004;1(5):357-366.     

I L- 15 trans-presentation regulates homeostasis of CD4^＋ T lymphocytes

Interleukin-15 （IL-15） is essential for the survival of memory CD8^＋ and CD4^＋ T cell subsets, and natural killer and natural killer T cells. Here, we describe a hitherto unreported role of IL-15 in regulating homoeostasis of naive CD4^＋ T cells. Adoptive transfer of splenocytes from non-obese diabetic （NOD） mice results in increased homeostatic expansion of T cells in lymphopenic NOD.scid.II15^-/- mice when compared to NOD.scid recipients. The increased accumulation of CD4^＋ T cells is also observed in NOD.II15^-/- mice, indicating that IL-15-dependent regulation also occurs in the absence of lymphopenia. NOD.scid mice lacking the I L- 15Ra chain, but not those lacking the common gamma chain, also show increased accumulation of CD4^＋ T cells. These findings indicate that the IL-15-mediated regulation occurs directly on CD4^＋ T cells and requires trans-presentation of IL-15. CD4^＋ T cells expanding in the absence of IL-15 signaling do not acquire the characteristics of classical regulatory T cells. Rather, CD4^＋ T cells expanding in the absence of IL-15 show impaired antigen-induced activation and IFN-7 production. Based on these findings, we propose that the IL-15-dependent regulation of the naive CD4^＋ T-cell compartment may represent an additional layer of control to thwart potentially autoreactive cells that escape central tolerance, while permitting the expansion of memory T cells.     

Computational Prediction and Identification of Epstein-Barr Virus Latent Membrane Protein 2A Antigen-Specific CD8^＋ T-Cell Epitopes

Epstein-Barr virus （EBV） associated nasopharyngeal carcinoma （NPC） is a high incidence tumor in Southeast Asia. Among EBV encoded proteins, latent membrane protein 2A （LMP2A） is an important antigen for T cell therapy of EBV. In this study, we predicted six HLA-A2 restricted CTL candidate epitopes of LMP2A by SYFPEITHI, NetMHC and MHCPred methods combined with the polynomial method. Subsequently, biological functions of these peptides were tested by experiments in vitro. In ELISPOT assay, the positive response of the LMP2A specific CTL stimulated by three （LMP2A264.272, LMP2A426-434 and LMP2A3s6.364） of six peptides respectively showed that the numbers of spots forming cells （SFC） ranged from 55.7 to 80.6 SFC/5 x 104 CO8^＋ T cells and the responding index （RI） ranged from 5.4 to 7. These three epitope-specific CTLs could effectively kill specific HLA-A2- expressing target cells. As a result, LMP2A264.272 （QLSPLLGAV）, LMP2A426.434 （CLGGLLTMV） and LMP2A356.364 （FLYALALLL） were identified as LMP2A-specific CD8^＋ T-cell epitopes. It would be useful to clarify immune response toward EBV and to develop a vaccine against EBV-correlative NPC.