急性乙型肝炎患者程序性细胞死亡受体1表达与记忆性T淋巴细胞形成的关系

目的 观察急性自限性乙型肝炎发病过程中患者体内病毒抗原特异性细胞毒性T淋巴细胞(CTL)上程序性细胞死亡受体1(PD-1)表达的动态变化特点及其与记忆性抗原特异性CD8+T淋巴细胞形成的关系. 方法 针对不同表位合成4种五聚体,长期随访收集11例人类白细胞抗原(HLA)-A2阳性的急性乙型肝炎患者的外周血,流式细胞仪检测病毒特异性CTL上免疫抑制性分子PD-1、记忆性分子(CCR7、CD45RA、CD127)和活化标志物CD38的表达情况,并分析其相关性.同时进行肝功能,HBsAg、抗-HBs和血清HBV DNA载量检测.结果所有急性自限性乙型肝炎患者发病早期均表现出高频度、病毒抗原多表位的特异性CTL反应,而晚期各表位CTL频率均明显下降.CTL上PD-1表达在早期明显上调;与早期比较,晚期PD-1分子的表达明显降低(t=4.314,P＜0.01).同时CTL高表达记忆性分子CCR7,CD45RA和CD127,而低表达活化标志物CD38.提示病毒清除后记忆性CD8+T淋巴细胞形成. 结论 在急性自限性乙型肝炎发病过程中,HBV特异性CTL上PD-1分子表达的动态变化与记忆性T淋巴细胞的形成密切相关.     

急性乙型肝炎患者体内巨细胞病毒特异性CD8 T细胞漂移的研究

目的通过观察急性乙型肝炎发病早期患者体内巨细胞病毒（CMV）CTL的数量和程序性细胞死亡受体1（PD-1）的表达水平,探讨该信号途径对CMVCTL频率和功能的影响。方法合成识别CMVV抗原表位的五聚体,同时采集12例HLA-A2阳性的急性乙型肝炎患者的外周血,用五聚体染色后,通过流式细胞仪分析CMVPP65表位特异性CTL的频率及其表面PD-1分子的表达特点,通过阻断PD-1/PD-L1信号途径的方法,探讨PD-1分子的表达对CMVCTL功能的影响。同时进行肝功能、HBsAg、抗-HBs和血清HBV DNA载量检测。结果急性乙型肝炎发病早期,患者体内CMVCTL的频率显著低于健康对照（P〈0.001）,同时PD-1分子的表达显著升高（P〈0.05）,该分子的上调表达与CMV特异性CD8T细胞的凋亡有关,而且阻断PD-1分子与其配体PD-L1的结合,能够有效恢复CMV特异性CD8T细胞分泌因子IFN-γ的能力。结论急性HBV感染造成异质性病毒CMVCTL的数量减少和功能降低,且免疫抑制性分子PD-1参与并调节了CMVCTL的数量减少和功能的降低,提示在人的病毒感染早期,免疫抑制性信号途径参与的删除前存在的记忆性CD8T细胞会为抵抗新病毒感染的抗原特异性T细胞提供更多的空间。     

乙型肝炎相关性肝功能衰竭患者外周血PD-1表达的临床意义

目的 观察乙型肝炎相关性肝功能衰竭患者细胞程序性死亡因子-1 (PD-1)表达特点及临床意义.方法 针对不同表位合成3种pentamer,采集16例急性和慢加急性肝功能衰竭患者外周血,并收集15例急性乙型肝炎(AHB)患者外周血作为对照,流式细胞仪分析各组病毒特异性CTL细胞的频率及其表面PD-1分子表达水平,同时观察与肝功能和血清HBV DNA载量的相关性.组间比较采用Mann-whitneyU检验.结果 与AHB患者比较,肝功能衰竭患者发病早期病毒特异性CD8 T淋巴细胞PD-1表达水平显著降低,该阶段PD-1表达水平与转氨酶呈显著正相关,但与病毒载量无明显相关性.随访发现,AHB患者早期,PD-1高水平表达,随着疾病康复,PD-1表达逐渐降低；而肝功能衰竭患者早期PD-1表达较低,随后显著增加,而后随着疾病恢复,PD-1进一步降低.结论 肝功能衰竭患者发病早期外周血PD-1表达水平较AHB患者显著降低,而PD-1延迟高表达则与急性肝功能衰竭的发生密切相关.     

慢性乙型肝炎患者特异性细胞毒性T淋巴细胞的变化

目的探讨慢性乙型肝炎急性发作及病情严重程度与特异性细胞毒性T淋巴细胞(CTL)水平的关系。方法从29例人白细胞抗原(HLA)-A2阳性慢性乙型肝炎急性发作及免疫耐受慢性乙型肝炎患者外周血中分离外周血单个核细胞,用HLA-A2*HBcAg抗原表位肽-五聚体复合体及CD8单克隆抗体染色后,用流式细胞仪检测乙型肝炎病毒(HBV)特异性的CTL细胞。并对6例急性发作患者进行动态检测HBV特异性的CTL、肝功能和病毒载量。结果19例急性发作慢性乙型肝炎患者五聚体阳性细胞占CD8阳性细胞的比例平均为1．4%±0．8%,而10例免疫耐受患者为0．6%±0．4%,两组间比较,t=2．180,P＜0．05,差异有统计学意义。急性发作导致重型肝炎的患者中,乙型肝炎核心抗原特异性CTL细胞阳性率平均为1．3%±1．0%,而非重型肝炎患者为1．4%±0．8%,两组间比较,差异无统计学意义。在12周的随访期内,患者丙氨酸氨基转移酶和病毒载量逐渐下降,但乙型肝炎核心抗原特异性CTL维持在较高的水平(＞0．7%)。结论慢性乙型肝炎患者急性发作与HBV特异性CTL有关,但主要的肝细胞损害可能并非直接由HBV特异性CTL引起的。     

慢性乙型肝炎患者树突状细胞诱导的HBV特异性细胞毒性T淋巴细胞PD-1的表达

目的 探讨慢性乙型肝炎(CHB)患者树突状细胞(DC)诱导的HBV特异性细胞毒性T细胞(CTL)表面程序性死亡受体1(PD-1)的表达情况及其与HBV DNA的关系.方法 采集30例CHB患者和10例健康人的抗凝外周静脉血,分离外周血单个核细胞(PBMC),在白细胞介素(IL)-4和粒-巨噬细胞集落刺激因子(GM-CSF)的作用下培养使DC增殖、成熟,培养第4d加入纯化的HBsAg进行冲击.采同一患者外周血,分离出自体T淋巴细胞,用含重组人白细胞介素(rhIL)-2的培养基维持T细胞的生长,培养第5d与HBsAg冲击的DC共培养.以流式细胞技术检测CTL的PD-1表达,并分析PD-1表达水平与HBV DNA的关系.结果 与健康对照组比较,CHB组DC诱导的HBV特异CTL的PD-1的表达明显升高(P=0.000).且HBeAg阳性组PD-1的表达率较HBeAg阴性组明显升高(P=0.000).CHB患者DC诱导的HBV特异性CTL的PD-1表达率与血清HBV DNA拷贝数的对数值呈正相关(r=0.53,P=0.008).结论 CHB患者DC诱导的HBV特异性CTL高表达PD-1分子,为HBV慢性感染过程中CTL功能低下,病毒难以清除提供了另一条重要线索.     

活动性慢性乙型肝炎患者特异性 CD8＋T 细胞转录因子 T-bet 表达及临床意义

目的：分析转录因子 T-bet 在活动性慢性乙型肝炎患者外周血 HBV 特异性 CD8＋ T 细胞中的表达及其临床意义。方法用 HBV 肽五聚体结合流式细胞仪检测 HLA-A2阳性的活动性慢性乙型肝炎患者和急性乙型肝炎患者外周血 HBV 特异性 CD8＋ T 细胞中 T-bet 的表达。比较分析 HBV 特异性 CD8＋ T 细胞中 T-bet 表达在急性、慢性乙型肝炎之间的差异,并进一步分析慢性乙型肝炎患者 HBV 特异性 CD8＋ T 细胞中 T-bet 表达与 HBV DNA 水平、ALT 水平以及临床预后之间的相关性。结果急性乙型肝炎患者外周血 HBV 特异性 CD8＋ T 细胞中 T-bet 表达水平显著高于活动性慢性乙型肝炎患者。活动性慢性乙型肝炎患者及 CHB 患者外周血 HBV 特异性 CD8＋ T 细胞中 T-bet 表达水平与 HBV DNA 水平及 ALT 水平无明显相关性,HBV 特异性 CD8＋ T 细胞中 T-bet 表达水平高的活动性慢性乙型肝炎患者发生HBeAg 血清转换率显著升高。结论活动性慢性乙型肝炎患者特异性 CD8＋ T 细胞转录因子 T-bet 表达与 HBV 感染的免疫控制密切相关。     

慢性乙型肝炎患者抗病毒治疗早期T细胞表面PD-1的表达

背景：慢性乙型肝炎病毒（HBV）感染者T细胞表面程序性死亡受体1（PD-1）呈持续性高表达。然而关于抗病毒治疗前后慢性乙型肝炎（CHB）患者T细胞表面PD-1表达变化及其与病毒载量关系的报道较少。目的：动态观察CHB患者抗病毒治疗早期外周血CD4＋和CD8＋T细胞表面PD-1表达水平,探讨其表达与血清HBV DNA载量和丙氨酸氨基转移酶（ALT）水平之间的关系。方法：以流式细胞术分别检测31例CHB患者抗病毒治疗前或基线期（T1）、治疗后4～8周（他）和12．16周（T3）的外周血CD4^＋和CD8^＋T细胞表面PD-1表达水平,以实时荧光定量聚合酶链反应（PCR）检测血清HBV DNA载量,同时检测血清ALT水平。结果：抗病毒治疗早期,CHB患者外周血CD4^＋和CD8^＋T细胞表面PD．1表达水平逐渐下调（P〈0．05）,血清HBV DNA载量和ALT水平亦逐步降低（P〈0．01）;CD4^＋和CD8^＋T细胞表面PD-1表达与HBV DNA载量（P〈0．01）和ALT水平（P〈0．05）均呈正相关。结论：有效的抗病毒治疗可通过降低CHB患者的病毒载量使T细胞表面PD-1表达下调,T细胞表面PD-1表达水平与患者疾病状态密切相关。     

重型肝炎患者乙型肝炎病毒特异性细胞毒性T淋巴细胞应答功能研究

目的 用主要组织相容性复合物（MHC）抗原肽四聚体（Tetramer）流式细胞技术，分析乙型重型肝炎患者外周血中特异性细胞毒性T淋巴细胞（CTL）应答状况，并探讨其临床意义。方法 采用Tetramer流式细胞技术检测乙型重型肝炎患者外周血中受人类白细胞抗原Ⅰ类分子限制的三类特异性CD8^＋CTL细胞数量；采用酶联免疫吸附斑点试验技术，测定经特异性乙型肝炎病毒（HBV）肽段诱导培养的特异性CTL表达膜内细胞因子IFNγ、TNFα、IL-4和IL—10等的水平；采用Promega CytoTox96非放射性细胞毒试验技术，测定经特异性HBV肽段诱导培养的特异性CTL杀伤靶细胞能力。结果 急性乙型重型肝炎组外周血中针对HBVcore18-27表位的特异性CTL数量高于慢性乙型重型肝炎组（P〈0．05），而低于急性乙型肝炎组（P〈0．05）；急性乙型重型肝炎组表达干扰素γ和肿瘤坏死因子α较慢性乙型重型肝炎组高（P值均〈0．05）；急性乙型重型肝炎组HBVcore18—27特异性CTL裂解靶细胞能力高于慢性乙型重型肝炎组（P〈0．05）。结论 急性乙型重型肝炎患者特异性CTL应答作用增强，而慢性乙型重型肝炎患者特异性CTI。应答缺乏。急性乙型重型肝炎患者外周血特异性CTL持续存在，可能与促进病毒清除等相关。     

乙型肝炎病毒核心区基因变异与机体细胞免疫水平的关系

HBV所激发的免疫应答和免疫病理反应是乙型肝炎发病机制的关键。其中细胞毒性T淋巴细胞（CTL）是细胞免疫反应的主要执行者，而针对HBcAg的CTL应答决定病毒是否被清除。当HBV基因发生变异，可改变氨基酸分子的表达，尤其当CTL识别的重要表位发生变异会改变机体对病毒的免疫反应。     

人类免疫缺陷病毒感染中的特异性细胞毒T淋巴细胞反应(一)

特异性细胞毒T淋巴细胞（Cytoxic T　Lympho-cyte,CTL）是一类可以杀伤表达特异性抗原靶细胞的T细胞亚群。CTL是抗细胞内感染（病毒、单核细胞增多性李斯特菌等）、急性同种异型移植物排斥反应和杀伤肿瘤的重要效应细胞[1]。 大多数CTL表达CD8分子,由其TCRαβ识别源于细胞内合成的外源抗原肽。该抗原肽自身MHC-I类分子形成复合物,在靶细胞表面上表达。近年的研究发现,HIV特异性CD8 T淋巴细胞是机体抗HIV的最主要的免疫细胞。这类细胞与被病毒感染的细胞特异性结合后,可以分泌各种细胞因子,杀死靶细胞。在艾滋病病毒感染的急性期,患者血浆病毒     

The immunoregulatory role of CD244 in chronic hepatitis B infection and its inhibitory potential on virus-specific CD8+ T-cell function

Multiple inhibitory receptors may play a role in the weak or absent CD8+ T-cell response in chronic hepatitis B virus (HBV) infection. Yet few receptors have been characterized in detail and little is known about their complex regulation. In the present study, we investigated the role of the signaling lymphocyte activation molecule (SLAM)-related receptor CD244 and of programmed death 1 (PD-1) in HBV infection in 15 acutely and 66 chronically infected patients as well as 9 resolvers and 21 healthy controls. The expression of CD244, PD-1, and T-cell immunoglobulin domain and mucin domain 3 (TIM-3) was analyzed in virus-specific CD8+ T-cells derived from peripheral blood or liver using major histocompatibility complex class I pentamers targeting immunodominant epitopes of HBV, Epstein-Barr-virus (EBV), or influenza virus (Flu). In chronic HBV infection, virus-specific CD8+ T-cells expressed higher levels of CD244 both in the peripheral blood and liver in comparison to the acute phase of infection or following resolution. CD244 was expressed at similarly high levels in EBV infection, but was low on Flu-specific CD8+ T-cells. In chronic HBV infection, high-level CD244 expression coincided with an increased expression of PD-1. The inhibition of the CD244 signaling pathway by antibodies directed against either CD244 or its ligand CD48 resulted in an increased virus-specific proliferation and cytotoxicity as measured by the expression of CD107a, interferon-γ, and tumor necrosis factor-α in CD8+ T-cells. Conclusion: CD244 and PD-1 are highly coexpressed on virus-specific CD8+ T-cells in chronic HBV infection and blocking CD244 or its ligand CD48 may restore T-cell function independent of the PD-1 pathway. CD244 may thus be another potential target for immunotherapy in chronic viral infections.     

SIV-specific CD8+ T cells express high levels of PD1 and cytokines but have impaired proliferative capacity in acute and chronic SIVmac251 infection

Programmed death-1 (PD-1) is a critical mediator of virus-specific CD8+ T-cell exhaustion. Here, we examined the expression of PD-1 on simian immunodeficiency virus (SIV)-specific CD8+ T cells and its possible involvement in regulation of cytokine production, proliferation, and survival of these cells. The majority of SIV-specific CD8+ T cells expressed a PD-1(high) phenotype, independent of their differentiation status, in all tissues tested. PD-1 expression gradually declined on CD8+ T cells specific for SIV-derived epitopes that had undergone mutational escape, indicating that antigen-specific TCR stimulation is the primary determinant of PD-1 expression. SIV-specific PD-1(high)CD8+ T cells produced IFN-gamma, TNF-alpha, and IL-2 under cognate peptide stimulation. While CD8+ T cells that proliferated in response to antigen had a PD-1(high) phenotype, it was determined that there was a reduced proliferative capacity of PD-1(high) compared with PD-1(low) SIV-specific CD8+ T cells. PD-1(high) SIV-specific CD8+ T cells were highly susceptible to cell death leading to loss of such cells after in vitro stimulation. Thus, PD-1 is a negative regulator of SIV-specific CD8+ T cells, operating predominantly through the induction of cell death. Manipulation of the interaction of PD-1 with its ligands could thus potentially restore the CD8+ T-cell responses in SIV infection.     

Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection

Inhibitory receptors play a crucial role in regulating CD8 T-cell function during chronic viral infection. T-cell Ig- and mucin-domain–containing molecule–3 (Tim-3) is well known to negatively regulate T-cell responses, but its role in CD8 T-cell exhaustion during chronic infection in vivo remains unclear. In this study, we document coregulation of CD8 T cell exhaustion by Tim-3 and PD-1 during chronic lymphocytic choriomeningitis virus infection. Whereas Tim-3 was only transiently expressed by CD8 T cells after acute infection, virus-specific CD8 T cells retained high Tim-3 expression throughout chronic infection. The majority (approximately 65% to 80%) of lymphocytic choriomeningitis virus–specific CD8 T cells in lymphoid and nonlymphoid organs coexpressed Tim-3 and PD-1. This coexpression of Tim-3 and PD-1 was associated with more severe CD8 T-cell exhaustion in terms of proliferation and secretion of effector cytokines such as IFN-γ, TNF-α, and IL-2. Interestingly, CD8 T cells expressing both inhibitory receptors also produced the suppressive cytokine IL-10. Most importantly, combined blockade of Tim-3 and PD-1 pathways in vivo synergistically improved CD8 T cell responses and viral control in chronically infected mice. Taken together, our study defines a parameter for determining the severity of CD8 T cell dysfunction and for identifying virus-specific CD8 T cells that produce IL-10, and shows that targeting both PD-1 and Tim-3 is an effective immune strategy for treating chronic viral infections.During chronic viral infection, virus-specific CD8 T cells become unresponsive to viral antigens and persist in a nonfunctional exhausted state (1). These exhausted CD8 T cells are characterized by the inability to produce immune-stimulatory cytokines, lyse virally infected cells, and proliferate (1). After CD8 T-cell exhaustion was initially characterized in the murine lymphocytic choriomeningitis virus (LCMV), such a functional impairment has been a common feature in human chronic viral infections such as, HIV, hepatitis B virus, and hepatitis C virus (HCV) (2). These functional defects in responding T cells are probably a primary reason for failure of immunological control of these persisting pathogens.Recent studies have focused on the crucial role of inhibitory receptors in regulating T-cell exhaustion during chronic viral infections. Programmed death 1 (PD-1), an inhibitory receptor of the CD28 superfamily, was shown to be highly expressed on exhausted CD8 T cells compared with functional memory T cells in the LCMV system, and in vivo blockade of this pathway restored the function of virus-specific CD8 T cells, resulting in enhanced viral control (3). Involvement of the PD-1 pathway has also been shown in various chronic viral infections including HIV, hepatitis B virus, and HCV in humans (4, 5), and during simian immunodeficiency virus infection in nonhuman primates (6). These studies have suggested that PD-1 could be a major inhibitory pathway during chronic infection and manipulation of this pathway may have therapeutic potential. However, blockade of PD-1 pathway does not completely restore T-cell function (4, 5, 7), indicating the involvement of other negative regulatory pathways in CD8 T-cell exhaustion. Gene expression profiling studies have identified the presence of a number of other potential inhibitory receptors on exhausted CD8 T cells such as 2B4, LAG-3, CTLA-4, PirB, GP49, and CD160 (8). Moreover, considerable evidence indicates that the expression of these receptors is important for regulating multiple functional aspects of CD8 T-cell exhaustion (7, 9). Therefore, a more thorough understanding of the importance of inhibitory receptors in CD8 T-cell exhaustion may reveal potential therapeutic targets leading to the restoration of CD8 T-cell function and better viral control.T-cell Ig- and mucin-domain–containing molecule-3 (Tim-3) was initially identified as a molecule expressed on T helper (Th) 1, but not Th2 (10). Interaction of Tim-3 with its ligand, galectin-9, regulates Th1 responses by promoting the death of Th1 cells and induces peripheral tolerance (11). Recently, it was reported that Tim-3 was expressed by virus-specific T cells during HIV-1 and HCV infections, and the expression levels correlated with the state of CD8 T-cell exhaustion (12, 13). In addition, blockade of Tim-3 improved the responsiveness of the exhausted T cells in vitro (12, 13), suggesting Tim-3 as another inhibitory marker of exhausted T cells during chronic viral infection. However, it is currently unclear whether Tim-3 regulates CD8 T cell exhaustion in cooperation with PD-1 during chronic viral infection. Furthermore, it will be important to explore the possibility of a synergistic effect of blocking both the Tim-3 and PD-1 pathways for providing new opportunities in antiviral therapy.In this study, we longitudinally investigated the expression of Tim-3 on virus-specific CD8 T cells during acute and chronic LCMV infection. We were especially interested in determining the coexpression of Tim-3 and PD-1 on CD8 T cells to identify populations with differential dysfunction during chronic viral infection. In addition, we examined the effect of in vivo blockade of Tim-3 and PD-1 regulatory pathways on the reversal of exhausted CD8 T cells and viral control.     

PD-1 up-regulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors

The immunoreceptor PD-1 is significantly up-regulated on exhausted CD8+ T cells during chronic viral infections such as HIV-1. However, it remains unknown whether PD-1 expression on CD8+ T cells differs between typical progressors (TPs) and long-term nonprogressors (LTNPs). In this report, we examined PD-1 expression on HIV-specific CD8+ T cells from 63 adults with chronic HIV infection. We found that LTNPs exhibited functional HIV-specific memory CD8+ T cells with markedly lower PD-1 expression. TPs, in contrast, showed significantly up-regulated PD-1 expression that was closely correlated with a reduction in CD4 T-cell number and an elevation in plasma viral load. Importantly, PD-1 up-regulation was also associated with reduced perforin and IFN-gamma production, as well as decreased HIV-specific effector memory CD8+ T-cell proliferation in TPs but not LTNPs. Blocking PD-1/PD-L1 interactions efficiently restored HIV-specific CD8+ T-cell effector function and proliferation. Taken together, these findings confirm the hypothesis that high PD-1 up-regulation mediates HIV-specific CD8+ T-cell exhaustion. Blocking the PD-1/PD-L1 pathway may represent a new therapeutic option for this disease and provide more insight into immune pathogenesis in LTNPs.     

程序性死亡受体-1在慢性病毒性肝炎中的作用

程序性死亡受体-1（PD-1）是用消减杂交技术从发生程序性死亡的T细胞株中分离得到的一种跨膜蛋白,是一种负向协同刺激分子。PD-1是活化T细胞表面的一种抑制性受体,与病毒特异性CD8^＋T细胞的功能耗竭有着密切关系。在乙型肝炎病毒和丙型肝炎病毒慢性感染过程中PD-1表达增强,阻断PD-1信号通路可以使耗竭的CD8^＋T细胞恢复免疫效应功能,有助于病毒清除,本文就PD-1与病毒性肝炎的关系及其在治疗中应用的前景作一综述。     

Antigen-specific CD4 T-cell help rescues exhausted CD8 T cells during chronic viral infection

CD4 T cells play a critical role in regulating CD8 T-cell responses during chronic viral infection. Several studies in animal models and humans have shown that the absence of CD4 T-cell help results in severe dysfunction of virus-specific CD8 T cells. However, whether function can be restored in already exhausted CD8 T cells by providing CD4 T-cell help at a later time remains unexplored. In this study, we used a mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection to address this question. Adoptive transfer of LCMV-specific CD4 T cells into chronically infected mice restored proliferation and cytokine production by exhausted virus-specific CD8 T cells and reduced viral burden. Although the transferred CD4 T cells were able to enhance function in exhausted CD8 T cells, these CD4 T cells expressed high levels of the programmed cell death (PD)-1 inhibitory receptor. Blockade of the PD-1 pathway increased the ability of transferred LCMV-specific CD4 T cells to produce effector cytokines, improved rescue of exhausted CD8 T cells, and resulted in a striking reduction in viral load. These results suggest that CD4 T-cell immunotherapy alone or in conjunction with blockade of inhibitory receptors may be a promising approach for treating CD8 T-cell dysfunction in chronic infections and cancer.     

Asthma death, CD8+ T cells, and viruses

Despite advances in the understanding of the pathophysiology of asthma and the availability of effective treatment, the World Health Organization estimates that asthma accounts for 1 in every 250 deaths worldwide. Viruses are associated with half of all asthma exacerbations. The immune response to viral infection may enhance preexisting airway inflammation via the release of chemokines and cytokines and local recruitment of inflammatory cells. Murine models have provided evidence for a deleterious role for CD8+ T cells in the context of respiratory viral infection. Passive transfer of respiratory syncytial virus-specific cytotoxic T lymphocytes (CTLs) to infected mice results in virus clearance, which is associated with acute and sometimes fatal pulmonary disease. Compared with control subjects, CD8+ cells appear to be preferentially sequestered in the airways of individuals with asthma during acute exacerbations. In addition, an expanded CD8+ T cell population, dominated by activated cytotoxic CD8+ lymphocytes, has been documented in biopsies from patients dying as a result of acute asthma in association with a viral infection. Undoubtedly, CD8+ CTLs are a crucial in cell-mediated immunity in response to respiratory viruses. However, it would appear that an aberrant CD8+ T cell response in the context of a viral infection may place individuals with asthma at risk for fatal asthma.     

HIV-1 specific CD8+ T cells with an effector phenotype and control of viral replication

Most people infected with HIV-1 cannot control viral replication despite the presence of virus-specific CD8+ T cells. It has been postulated that this inability is related to the failure of these cells to mature into fully differentiated effector cells. We tested this hypothesis by comparing the maturation phenotype of virus-specific CD8+ T cells in people who could control viral replication off anti-retroviral therapy with those who could not. In five patients with treated acute HIV-1-infection, structured treatment interruption (STI) induced control of viral replication was associated with expansion of virus-specific CD8+ T cells with a fully differentiated effector phenotype. These effector cells were also expanded in treatment-naive chronically infected individuals who spontaneously controlled viral replication, and augmented expression of perforin was noted in both settings. Our data show that full maturation of virus-specific CD8+ T cells is possible in the context of HIV-1-infection, and suggest that such maturation might be important in viral control.