Activation-induced cell death in T cells

Summary: A properly functioning immune system is dependent on programmed cell death at virtually every stage of lymphocyte development and activity. This review addresses the phenomenon of activation‐induced cell death (AICD) in T lymphocytes, in which activation through the T‐cell receptor results in apoptosis. AICD can occur in a cell‐autonomous manner and is influenced by the nature of the initial T‐cell activation events. It plays essential roles in both central and peripheral deletion events involved in tolerance and homeostasis, although it is likely that different forms of AICD proceed via different mechanisms. For example, while AICD in peripheral T cells is often caused by the induction of expression of the death ligand, Fas ligand (CD95 ligand, FasL), it does not appear to be involved in AICD in thymocytes. This and other mechanisms of AICD are discussed. One emerging model that may complement other forms of AICD involves the inducible expression of FasL by nonlymphoid tissues in response to activated T lymphocytes. Induction of nonlymphoid FasL in this manner may serve as a sensing mechanism for immune cell infiltration, which contributes to peripheral deletion.     

Activation-induced cell death in T cells and autoimmunity

Activation-induced cell death (AICD), which results from the interaction between Fas and Fas ligand, is responsible for maintaining tolerance to self-antigen. A defect in AICD may lead to development of autoimmunity. During the last several years, much progress has been made in understanding the mechanism(s) of AICD and its potential role in the pathogenesis of autoimmune diseases. In this review, we summarize the most recent progress on the regulation of the susceptibility of T cells to AICD and its possible involvement in autoimmune diseases.     

Activation-induced NK cell death triggered by CD2 stimulation

Both T cells and natural killer (NK) cells express CD2, the target of an alternative activation pathway that induces the proliferation of both cell types. The mitogenic response to CD2 ligation requires the co-expression of CD3 : TCR in T cells and FcγRIII in NK cells, suggesting that these receptors are involved in transducing the response initiated by CD2. The ability of FcγRIII to trigger the activation-induced death of IL-2-primed NK cells led us to investigate the potential for CD2 to trigger activation-induced NK cell death. Our results reveal that the same anti-CD2 monoclonal antibodies (mAb) that activate freshly isolated NK cells induce apoptosis in IL-2-primed NK cells. CD2-induced apoptosis results in chromatin condensation, DNA fragmentation and cleavage of caspase-3. Activation-induced NK cell death triggered by CD2 ligation is extremely rapid (DNA fragmentation is first observed at 90 min) and it is not inhibited by neutralizing antibodies reactive with TNF-α or Fas ligand. Whereas mAb reactive with distinct CD2 epitopes (i.e. T11.1, T11.2, and T11.3) are required for activation-induced T cell death, mAb reactive with a single CD2 epitope are sufficient for activation-induced NK cell death. The ability of CD2, CD16, and CD94 to induce apoptosis in IL-2-primed lymphocytes suggests that cytokine priming changes the response to a signaling cascade that is common to each of these activation receptors.     

AICD与病毒感染

因缺乏必要的存活信号而发生凋亡(apoptosis)几乎是所有体细胞的一个共同特征,但T细胞可以经受另种特殊的凋亡,即"激活诱导细胞死亡(activation-inducedcelldeath,AICD)"。本文在阐述AICD的发生机理及一般意义的基础上,重点讨论其与病毒感染的关系。     

Activation-induced cell death (apoptosis) of mature peripheral T lymphocytes

Programmed cell death (apoptosis) is triggered in immature thymocytes and T-cell hybridomas by signalling via the CD3-T-cell receptor pathway. In this paper, Dieter Kabelitz and colleagues catalogue the recently accumulating evidence that apaptosis can also be initiated in mature peripheral T cells this may constitute an important aspect of cellular immune regulation.     

Activation-induced T cell death occurs at G1A phase of the cell cycle

Peripheral negative selection of cycling T cells after TCR engagement and deletion of activated T cells after an immune response occur by an apoptotic process termed activation-induced cell death (AICD). The cross-linking of TCR-CD3 complex with anti-CD3 monoclonal antibody led to significant apoptotic cell death in peripheral blood T cells. To further define cell cycle restriction points for triggering AICD in T cells, we evaluated the association between cell cycle progression and death signal transduction. Simultaneous DNA / RNA quantification analysis revealed that T cells entering G1A phase of the cell cycle may acquire sensitivity to AICD. The activation of caspase-3 was induced when T cells entered G1A phase. Up-regulation of cyclin-dependent kinases (Cdk4 and Cdk6) and cyclin D3 was initiated in TCR-stimulated T cells entering G1A phase and expression of these markers steadily increased as T cells progressed from G1A into G1B phase. Interestingly, caspase-3 inhibitors could inhibit the up-regulation of these G1 cell cycle regulators and induce G0 / G1A arrest as well as the inhibition of AICD. On the basis of these results, AICD signals are most likely transduced into TCR-stimulated T cells entering G1A phase. T cells that fail to progress from G1A into G1B phase undergo AICD.     

Activation-induced cell death of human melanoma specific cytotoxic T lymphocytes is mediated by apoptosis-inducing factor

Activation-induced cell death (AICD) of T cells can be an impediment towards achieving a robust and long-lived cytolytic T lymphocyte (CTL) response from active specific immunization or after adoptive cell transfer in cancer immunotherapy. The mechanism of AICD in primary CTL, however, remains poorly understood. It is widely believed that AICD is driven by signals from death receptors (DR) and that the cell death takes place in a caspase-dependent manner, although it has been shown that AICD of T cells can be induced by internal triggers and that death takes place in a caspase-independent manner. We show here that AICD in human melanoma epitope-specific primary CTL involves selective mitochondrio-nuclear translocation of the apoptosis inducing factor (AIF) without cytochrome c release, caspase-3 and caspase-8 activation, and results from large-scale DNA fragmentation. The c-jun-N terminal kinase (JNK) inhibitor, SP600125, blocks the mitochondrio-nuclear translocation of AIF and prevents AICD in these CTL. These findings suggest that the AICD in human melanoma epitope specific primary CTL is mediated by mitochondrial AIF release and JNK is involved in regulation of this death process.     

Activation-induced cell death of human T-cell subsets is mediated by Fas and granzyme B but is independent of TNF-alpha.

Human primary effector T cells were analyzed for their susceptibility to anti-CD3-induced activation-induced cell death (AICD). Th1 and Tc1 cells were more susceptible to AICD than their type 2 counterparts. Type 1 and type 2 subsets were also found to be differentially susceptible to CD95-mediated apoptosis, although cell-surface expression of CD95 and CD95L was at similar levels on all subsets. A role for CD95 in AICD was confirmed by the addition of anti-CD95L antibodies that partially abrogated AICD. Residual apoptosis could not be accounted for by TNF-alpha/TNFR interactions because although type 1 cells secreted more TNF-alpha than type 2 cells, the addition of TNFR:Fc fusion protein did not inhibit AICD. Instead, a reduction in AICD was observed in the presence of EGTA or concanamycin A. The inhibition of apoptosis by a granzyme B inhibitor z-AAD-CMK in Tc1 cells further indicated an involvement of the granule exocytosis mechanism in AICD.     

Activation-induced apoptosis in lymphoid systems.

Lymphocytes become activated when antigen receptors on the cell surface are cross-linked, or when they are exposed to agents that mimic this signal. Although such activation is usually associated with the production of immune mediators (e.g. antibodies, cytokines) and entry into the cell cycle, it can alternatively lead to death via apoptosis. This activation-induced apoptosis was first observed in developing lymphocytes and has been proposed as a mechanism for negative selection, by which immature cells with potential for autoreactivity are eliminated from the maturation pathway. Activation-induced apoptosis has also been observed in normal, mature lymphocytes under some conditions, and this may account for the phenomena of peripheral deletion, in which mature T cells are eliminated upon exposure to high doses of antigen. It may also be an important mechanism whereby CD4+ T cells are depleted in HIV+ individuals. Although the phenomenon of activation-induced apoptosis is not understood, recent studies have begun to implicate specific signal transduction pathways and gene products in the process. Among the latter is the c-myc proto-oncogene, which paradoxically can play an essential role in several forms of apoptosis, including that induced by activation of lymphocytes.     

Activation-induced T cell death, and aberrant T cell activation via TNFR1 and CD95-CD95 ligand pathway in stable cardiac transplant recipients

Specific blockade by antibodies (Abs) utilized in induction therapy may cause activation-induced cell death (AICD) in lymphocytes of transplant recipients, preactivated via CD95 and tumour necrosis factor-alpha receptor type 1 (TNFR1), and reduce allograft rejection frequency. Amongst 618 heart transplant (HTX) patients receiving antithymocytes globulin (ATG) therapy, 14 recipients with IVUS-verified freedom of transplant vasculopathy were studied. The control group contained 14 patients awaiting transplantation, classified by the New York Hearth Association heart failure as class IV. From 618 HTX patients 89% were free of rejection grade ISHLT > or =2-3 within 3-month post transplantation and 86% after one year. The death inducing receptors (DIR) such as CD95, CD95L and soluble TNFR1 were significantly increased in HTX recipients versus controls, as demonstrated by FACS, immunoblotting or ELISA (P < 0.001). The presence of increased DIR and in vivo apoptosis in HTX recipients, indicated by annexin-V binding, was further confirmed by the presence of high concentration of histones in the sera of patients. ATG, anti-IL-2R and OKT-3 Abs inhibited cell proliferation in a dose-dependent manner. The induction of apoptosis and/or necrosis was demonstrated in cells cultured with these Abs by annexin-V and 7-aminoactinomycin staining, respectively. Our findings demonstrate that T cells from HTX recipients express high level of CD95, CD95L and soluble TNFR1, and undergo apoptosis and AICD. These cells recognizing donor alloantigens may be selectively eliminated in vivo, and should be responsible for the observed immunological unresponsiveness, indicated by low rejection rates in our patient cohort treated by conventional triple therapy.     

Activation-induced peripheral blood T cell apoptosis is Fas independent in HIV-infected individuals

T cell apoptosis has been proposed as an Important contributorto the functional defects and depletion of T cells in HIV-lnfectedIndividuals. However, the mechanisms Involved in this apoptosishave not been elucidated. We recently showed that peripheralblood T cells from HIV-infected individuals are especially susceptibleto Fas antigen-induced apoptosis. In this study we examine therole of Fas, CTLA-4, tumor necrosis factor (TNF) receptors (TNFR)and CD30, receptors known to be involved In T cell activation-inducedcell death (AICD), in the spontaneous and activation (anti-CD3)-lnducedapoptosis of peripheral blood T cells from asymptomatic HIV-infectedindividuals. We report here that spontaneous and activation-InducedT cell apoptosis cannot be inhibited by reagents that blockinteractions of Fas, CTLA-4, p55 and p75 TNFR and CD30 withtheir respective ligands. We also show that IL-12, IFN-, IL-4and IL-10 cannot modify spontaneous, activation- and anti-Fas-inducedapoptosis. Anti-Fas preferentially Induced CD4⁺ T cell apoptosiswhereas AICD induced apoptosis equally In CD4⁺ and CD8⁺ T cells.We conclude that T cell AICD In HIV infection Is not mediatedby Fas, thus Indicating that Fas-Induced and activation-InducedT cell apoptosis are independent mechanisms of apoptosis whichmay play different roles in the pathogenesls of HIV infection.     

Activation-induced changes in peptides presented by T cells.

We compared the sets of peptides presented via HLA Class I in a CD4 + T cell line (Jurkat) before and after activation with PMA plus PHA.

We found that cell activation resulted in the de n vo presentation of some peptides.

Sequence analysis revealed that one of the newly presented peptides derived from IL-1 receptor antagonist (IL-1ra).

Since IL-1ra was not known to be expressed by lymphocytes, we also investigated ist pattern of expression in lymphocytes of the T lineage.

RT-PCR analysis allowed us to demonstrate that IL-1ra is expressed upon activation in Jurkat cells, in CD4+ lymphocytes from peripheral blood, but not in CD8+ ones, and in thymocytes.

This suggests that activation in CD4+ T cells is followed by the novo presentation of peptides der ved from proteins expressed only upon activation. Interestingly, of the two forms of IL-1ra expre sed in different cell lineages, the intracellular one and the secreted one, only the former is expre sed in activated CD4+ cells.     

吞噬作用能促进线虫的程序性细胞死亡

在后生动物的发育中 ,程序性细胞死亡 (ＰＣＤ)在组织的塑型、神经元间的精细连接、多余细胞或损伤细胞的消除等诸多方面扮演重要角色。通过ＰＣＤ方式 ,正在死亡的细胞迅速被吞噬细胞包裹清除。在线虫体内 ,ＰＣＤ需要杀手基因 (ｋｉｌｌｅｒｇｅｎｅｓ)ｅｇｌ- 1、ｃｅｄ - 4和ｃｅｄ - 3等的协同作用 ,而正在死亡细胞的吞噬过程 (ｅｎｇｕｌｆｍｅｎｔ)则由ｃｅｄ - 1、ｃｅｄ -2、ｃｅｄ - 5、ｃｅｄ - 6、ｃｅｄ - 7、ｃｅｄ - 10、ｃｅｄ - 12等吞噬基因 (ｅｎｇｕｌｆｍｅｎｔｇｅｎｅｓ)协同完成。根据基因相互作用的基础 ,将线虫的…     

Relationship of cell death to cyclophosphamide-induced ocular malformations.

C57BL/6J mice were used to study the ocular teratogenic effects of cyclophosphamide administered to pregnant females on d 9 of pregnancy at a dose of 5 mg/kg body weight. Nile blue staining demonstrated increased cell death at the base of the optic stalk, in the optic vesicle, and in the perivesicular mesenchyme in treated embryos. Malformations studied at gestational d 11 and 16 by light and scanning electron microscopy included microphthalmos, microphakia, and aphakia and were predictable based upon patterns of increased cell death. These anomalies are similar to those reported with exposure to ethanol or isotretinoin on gestational d 7.     

Evidence of apoptotic cell death in HIV encephalitis.

The mechanism of cell death in the brains of patients with acquired immune deficiency syndrome was examined in 15 cases, 8 of whom had human immunodeficiency virus (HIV) encephalitis, and in 8 control cases. Postmortem formalin-fixed, paraffin-embedded sections were prepared for routine histology and immunohistochemistry to detect cell-specific antigens. Apoptosis was detected by its morphology and by in situ end labeling of its characteristic oligonucleosomal fragments. Combined in situ end labeling and immunohistochemistry identified specific cell types. Six acquired immune deficiency syndrome brains, 5 of which had HIV encephalitis, contained positive nuclei by in situ end labeling. Co-labeling studies identified the cells as neurons, reactive astrocytes, and, rarely, the multinucleated giant cells of HIV encephalitis. The only control with nuclei positive by in situ end labeling had hepatic encephalopathy and Alzheimer type II astrocytes; the location and absence of cell-specific markers suggested a glial origin for the labeled cells. These results demonstrate that at least some neuronal and astrocytic death in HIV infection occurs by apoptosis. Its stimuli are unknown, but likely candidates include tumor necrosis factor or HIV viral products. Additionally, we hypothesize that apoptotic death of reactive astrocytes may be a normal mechanism whereby the brain removes an excess number of astrocytes that have proliferated after certain types of brain injury.