Defective CD8 T cell memory following acute infection without CD4 T cell help

The CD8+ cytotoxic T cell response to pathogens is thought to be CD4+ helper T cell independent because infectious agents provide their own inflammatory signals. Mice that lack CD4+ T cells mount a primary CD8 response to Listeria monocytogenes equal to that of wild-type mice and rapidly clear the infection. However, protective memory to a challenge is gradually lost in the former animals. Memory CD8+ T cells from normal mice can respond rapidly, but memory CD8+ T cells that are generated without CD4 help are defective in their ability to respond to secondary encounters with antigen. The results highlight a previously undescribed role for CD4 help in promoting protective CD8 memory development.     

Preserved CD4+ central memory T cells and survival in vaccinated SIV-challenged monkeys

Vaccine-induced cellular immunity controls virus replication in simian immunodeficiency virus (SIV)-infected monkeys only transiently, leading to the question of whether such vaccines for AIDS will be effective. We immunized monkeys with plasmid DNA and replication-defective adenoviral vectors encoding SIV proteins and then challenged them with pathogenic SIV. Although these monkeys demonstrated a reduction in viremia restricted to the early phase of SIV infection, they showed a prolonged survival. This survival was associated with preserved central memory CD4+ T lymphocytes and could be predicted by the magnitude of the vaccine-induced cellular immune response. These immune correlates of vaccine efficacy should guide the evaluation of AIDS vaccines in humans.     

A role for CD40 expression on CD8+ T cells in the generation of CD8+ T cell memory

The delivery of CD4 help to CD8+ T cell responses requires interactions between CD40 and CD40 ligand and is thought to occur through antigen-presenting cell (APC) activation. Here we show that generation of memory CD8+ T cells displaying an enhanced capacity for cell division and cytokine secretion required CD4 help but not CD40 expression by the APCs. Activated CD4+ and CD8+ T cells expressed CD40; and in the absence of this protein, CD8+ T cells were unable to differentiate into memory cells or receive CD4 help. These results suggest that, like B cells, CD8+ T cells receive CD4 help directly through CD40 and that this interaction is fundamental for CD8+ T cell memory generation.     

Linear differentiation of cytotoxic effectors into memory T lymphocytes

A central question in immunology is the origin of long-lived T cell memory that confers protection against recurrent infection. The differentiation of na?ve T cell receptor transgenic CD8+ cells into effector cytotoxic T lymphocytes (CTLs) and memory CD8+ cells was studied. Memory CD8+ cells that were generated after strong antigenic stimulation were the progeny of cytotoxic effectors and retained antigen-specific cytolytic activity 10 weeks after adoptive transfer to antigen-free recipient mice. Thus, potential vaccines based on CTL memory will require the differentiation of na?ve cells into post-effector memory T cells.     

Regulation of antigen-specific CD8+ T cell homeostasis by perforin and interferon-gamma

T cell memory depends on factors that regulate expansion and death of these cells after antigenic stimulation. Mice deficient in perforin and interferon-gamma (IFN-gamma) exhibited increased expansion, altered immunodominance, and decreased death of antigen-specific CD8+ T cells after infection with an attenuated strain of Listeria monocytogenes, which was cleared from these mice. Expansion of CD8+ T cells was controlled by perforin, whereas IFN-gamma regulated immunodominance and the death phase. Thus, perforin and IFN-gamma regulate distinct elements of CD8+ T cell homeostasis independently of their role as antimicrobial effector molecules.     

Dendritic cell-induced memory T cell activation in nonlymphoid tissues

Secondary lymphoid organs are dominant sites of T cell activation, although many T cells are subsequently retained within peripheral tissues. Currently, these nonlymphoid compartments are viewed as sites only of effector T cell function, without the involvement of renewed induction of immunity via the interactions with professional antigen-presenting cells. We describe a method of reactivation of herpes simplex virus to examine the stimulation of tissue-resident T cells during secondary challenge. The results revealed that memory CD8+ T cell responses can be initiated within peripheral tissues through a tripartite interaction that includes CD4+ T cells and recruited dendritic cells. These findings lend evidence for the existence of a sophisticated T cell response mechanism in extra-lymphoid tissues that can act to control localized infection.     

Requirement for CD4 T cell help in generating functional CD8 T cell memory

Although primary CD8 responses to acute infections are independent of CD4 help, it is unknown whether a similar situation applies to secondary responses. We show that depletion of CD4 cells during the recall response has minimal effect, whereas depletion during the priming phase leads to reduced responses by memory CD8 cells to reinfection. Memory CD8 cells generated in CD4+/+ mice responded normally when transferred into CD4-/- hosts, whereas memory CD8 cells generated in CD4-/- mice mounted defective recall responses in CD4+/+ adoptive hosts. These results demonstrate a previously undescribed role for CD4 help in the development of functional CD8 memory.     

雏鸡免疫柔嫩艾美耳球虫早熟株和毒株的细胞免疫反应

AA肉鸡雏鸡分别经口免疫柔嫩艾美耳球虫毒株早熟株，用免疫组化ABC法染色检测小肠、盲肠扁桃体、脾脏中CD4^ 、CD8^ T淋巴细胞动态变化；用淋巴细胞转化实验MTT法检测T淋巴细胞活性。结果表明：球虫免疫鸡后，CD4^ T淋巴细胞在一次免疫后迅速增殖，第6天达到第一峰，免疫柔嫩艾美耳球虫毒株的鸡盲肠与脾脏中CD4^ T淋巴细胞占所有淋巴细胞百分率分别达到38％和44％，免疫早熟株的鸡盲肠与脾脏中CD4^ T淋巴细胞占所有淋巴细胞百分率分别达到36％和43％，而二次免疫后和对照相比很少有显著差异。CD8^ T淋巴细胞在一次免疫后比CD4^ T增殖速度慢，第9天达到第一峰。免疫柔嫩艾美耳球虫毒株的鸡在此日盲肠与脾脏中CD8^ T淋巴细胞占所有淋巴细胞百分率分别达到37％和47％，免疫早熟株的鸡在此日盲肠与脾脏中CD8^ T淋巴细胞占所有淋巴细胞百分率分别达到36％和48％，二次免疫后迅速大量增殖，免疫柔嫩艾美耳球虫毒株的鸡在二免后第2天盲肠与脾脏中CD8^ T淋巴细胞占所有淋巴细胞百分率分别达到39％和50％．免疫柔嫩艾美耳球虫早熟株的鸡在二免后第2天盲肠与脾脏中CD8^ T淋巴细胞占所有淋巴细胞百分率分别达到37％和50％。且CD8^ T淋巴细胞总体水平比CD4^ T淋巴细胞多。盲肠扁桃体中T细胞的增殖速度比其他组织更快。免疫早熟株的鸡与免疫毒株的鸡肠道黏膜中的CD4^ 、CD8^ T淋巴细胞变化基本一致。一次免疫鸡比未免疫对照T淋巴细胞活性显著升高；进行二免的鸡免疫后第一、二、三周T淋巴细胞活性均比未进行二免的鸡显著升高；毒株免疫鸡T淋巴细胞活性大多与早熟株免疫鸡无8显著差异。     

Demethylated CD8 gene in CD4+ T cells suggests that CD4+ cells develop from CD8+ precursors

Mature T cells and medullary thymocytes bear either the CD4 or CD8 differentiation antigen. Precursor cells in the thymus express neither CD4 nor CD8 (CD4-8-), but most cortical thymocytes are CD4+8+. Whether CD4+ and CD8+ mature T cells arise directly from CD4-8- precursors or from a CD4+8+ intermediate remains unresolved. In this study, methylation of the CD8 gene in murine T cells and thymocytes was examined. There was progressive demethylation of the CD8 gene in the thymus during the transition from CD4-8- to CD4+8+. A similar pattern of demethylation of the CD8 gene was seen in CD4+ mature T cells, suggesting previous expression of CD8 in the CD4+ lineage.     

Control of homeostasis of CD8+ memory T cells by opposing cytokines

Memory T cells maintain their numbers for long periods after antigen exposure. Here we show that CD8+ T cells of memory phenotype divide slowly in animals. This division requires interleukin-15 and is markedly increased by inhibition of interleukin-2 (IL-2). Therefore, the numbers of CD8+ memory T cells in animals are controlled by a balance between IL-15 and IL-2.     

CD8alphaalpha-mediated survival and differentiation of CD8 memory T cell precursors

Memory T cells are long-lived antigen-experienced T cells that are generally accepted to be direct descendants of proliferating primary effector cells. However, the factors that permit selective survival of these T cells are not well established. We show that homodimeric alpha chains of the CD8 molecule (CD8alphaalpha) are transiently induced on a selected subset of CD8alphabeta+ T cells upon antigenic stimulation. These CD8alphaalpha molecules promote the survival and differentiation of activated lymphocytes into memory CD8 T cells. Thus, memory precursors can be identified among primary effector cells and are selected for survival and differentiation by CD8alphaalpha.     

Preferential localization of effector memory cells in nonlymphoid tissue

Many intracellular pathogens infect a broad range of host tissues, but the importance of T cells for immunity in these sites is unclear because most of our understanding of antimicrobial T cell responses comes from analyses of lymphoid tissue. Here, we show that in response to viral or bacterial infection, antigen-specific CD8 T cells migrated to nonlymphoid tissues and were present as long-lived memory cells. Strikingly, CD8 memory T cells isolated from nonlymphoid tissues exhibited effector levels of lytic activity directly ex vivo, in contrast to their splenic counterparts. These results point to the existence of a population of extralymphoid effector memory T cells poised for immediate response to infection.     

Inhibition of T cell receptor expression and function in immature CD4+CD8+ cells by CD4

Most immature CD4+CD8+ thymocytes express only a small number of T cell receptor (TCR) molecules on their surface, and the TCR molecules they do express are only marginally capable of transducing intracellular signals. TCR expression and function was not intrinsically low in immature CD4+CD8+ thymocytes, but was found to be actively inhibited by CD4-mediated signals. Indeed, release of CD4+CD8+ thymocytes from CD4-mediated signals resulted in significant increases in both TCR expression and signaling function. These results suggest that, in CD4+CD8+ cells developing in the thymus, increased TCR expression and function requires release from CD4-mediated inhibition.     

Integrase inhibitors and cellular immunity suppress retroviral replication in rhesus macaques

We describe the efficacy of L-870812, an inhibitor of HIV-1 and SIV integrase, in rhesus macaques infected with the simian-human immunodeficiency virus (SHIV) 89.6P. When initiated before CD4 cell depletion, L-870812 therapy mediated a sustained suppression of viremia, preserving CD4 levels and permitting the induction of virus-specific cellular immunity. L-870812 was also active in chronic infection; however, the magnitude and durability of the effect varied in conjunction with the pretreatment immune response and viral load. These studies demonstrate integrase inhibitor activity in vivo and suggest that cellular immunity facilitates chemotherapeutic efficacy in retroviral infections.     

三群商品代蛋鸡J亚群白血病跟踪观察

【目的】了解J亚群白血病在海兰褐蛋鸡群中发生和发展的真实表现及其与病毒分离和抗体反应的关系；【方法】对来自3个鸡场39至43周龄31只疑似ALV-J感染鸡做了连续两个月的临床、病理、病毒血症和抗体反应动态观察和比较；【结果】这3群鸡对ALV-J感染率非常高，有28只鸡在死前感染ALV-J或呈现持续性病毒血症，其中14只表现为无抗体反应的免疫耐受性持续性病毒血症。这3群鸡都表现为典型J亚群白血病髓细胞样肿瘤特征性病变，且在几乎所有不同脏器和组织均可出现。在31只鸡中，有13只鸡同时在3个或3个以上不同脏器中出现肿瘤/血管瘤，有1只鸡出现在5个器官中；【结论】中国近年来不仅仍有ALV-J在蛋鸡群中流行，而且在过程中，ALV-J致病性逐渐增强。     

丙肝感染宿主亲嗜性基因OCLN和CD81在猕猴川西亚种组织中的分布

丙型肝炎动物模型缺乏限制了丙型肝炎的研究,如果与人类基因背景相似的猕猴能作为丙型肝炎动物模型将有重大意义。文章拟通过检测决定HCV感染物种特异性的关键基因OCLN与CD81在猕猴不同组织的表达量,并以HCV易感的人肝癌细胞系Huh 751为对照,来探究猕猴作为丙型肝炎动物模型的可能性。结果表明,OCLN与CD81在猕猴川西亚种的肝脏、脾脏、肺脏、淋巴结和脊髓中均有表达,但表达量均极显著低于在Huh 751细胞系中的表达量（P<0.01）。肝脏中的OCLN表达量略低于肺脏中的表达量,而肝脏CD81的表达量均高于其他组织。并且,OCLN在不同组织中的表达水平与人体OCLN表达规律相符合（脾＜肝＜肺）。该结果提示HCV感染的宿主亲嗜性基因OCLN与CD81在猕猴中的低表达量可能导致HCV不能有效地结合组织靶细胞,因此推测,猕猴不能直接用于丙型肝炎动物造模可能与此有关。今后可通过转基因等技术增强OCLN与CD81基因的表达,从而使猕猴获得直接感染HCV的能力。     

兔脑炎微孢子虫感染对家兔细胞免疫功能的影响

以临床症状和病理学变化确诊为兔脑炎微孢子虫感染的家兔为研究对象,用流式细胞计数仪检测外周血CD4+、CEB+细胞比例,并与健康家兔进行比较。结果表明兔脑炎微孢子虫病患兔外周血CD4+细胞比例与对照组相比无明显变化,P>0.05;而CD8+细胞比例明显高于对照组,CD4+/CD8+比值则明显低于对照组,P<0.05。提示兔脑炎微孢子虫患兔外周血CD4+/CD8+比值明显下降,机体免疫力减弱,可能是导致兔脑炎微孢子虫入侵机体,引起家兔发病的重要原因。     

胸膜肺炎放线杆菌感染对猪外周血T淋巴细胞亚群及增殖影响

为研究感染APP对猪外周血免疫功能影响,将24头健康杜洛克、长白猪和约克夏三元杂交(DLY)仔猪按性别、体重分为2组,分别用生理盐水(对照组CG)和含3.8×107CFU.mL-1猪放线杆菌(APP)稀释液(试验组TG)喷雾鼻腔。结果表明,TG猪血液中白细胞总数(WBC)、中性粒细胞数(GRA)、中间细胞数(MID)均极显著升高(P<0.01),淋巴细胞数(LYM)却极显著降低(P<0.01)。TG猪外周血CD3+T细胞降低(P>0.05),CD3+CD4+T细胞极显著降低(P<0.01),CD3+CD8+T细胞及CD4+/CD8+值显著降低(0.010.05)。结果表明,感染放线杆菌后,猪整体防御机能和呼吸道粘膜局部免疫功能增强,而机体整体免疫功能下降。