Interleukin-1 beta converting enzyme-like protease involvement in Fas-induced and activation-induced peripheral blood T cell apoptosis in HIV infection. TNF-related apoptosis-inducing ligand can mediate activation-induced T cell death in HIV infection.
Interleukin-1 beta converting enzyme-like protease involvement in Fas-induced and activation-induced peripheral blood T cell apoptosis in HIV infection. TNF-related apoptosis-inducing ligand can mediate activation-induced T cell death in HIV infection.
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DOI：
10.1084/jem.186.8.1365
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发表时间：
1997-10-20
期刊：
影响因子：
--
通讯作者：
Herzenberg LA
中科院分区：
文献类型：
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作者：
Katsikis PD;Garcia-Ojeda ME;Torres-Roca JF;Tijoe IM;Smith CA;Herzenberg LA;Herzenberg LA
外周血T细胞凋亡在人类免疫缺陷病毒（HIV）感染的发病机制中起重要作用。HIV感染者的外周血单个核细胞培养物中均描述了自发的、Fas（CD 95）诱导的和活化诱导的T细胞凋亡。我们以前已经表明，激活诱导的T细胞凋亡是Fas独立的外周血T细胞从HIV+个人。在这项研究中，我们通过使用白细胞介素-1 β转化酶（ICE）同源物的抑制剂来扩展和证实这些观察结果。我们发现，z-VAD-favorites，ICE同源物的三肽抑制剂，可以抑制Fas诱导的外周血CD 4+和CD 8 + T细胞的无症状HIV+个体的凋亡。在一些但不是所有无症状的HIV+个体中，z-VAD-fatal还抑制活化（抗CD 3）诱导的CD 4+和CD 8 + T细胞凋亡（AICD）。多参数流式细胞术检测细胞凋亡。z-VAD-fatal抑制剂还增强了抗Fas或抗CD 3抗体处理的培养物中T细胞的存活并抑制DNA片段化。可被z-VAD-favorites抑制的AICD是Fas非依赖性的，并且可被肿瘤坏死因子相关凋亡诱导配体（TRAIL）的阻断性单克隆抗体抑制，TRAIL是最近描述的TNF/神经生长因子配体家族的成员。以上结果表明，Fas诱导的T细胞凋亡在HIV感染中是ICE依赖性的。在某些患者中，ICE抑制剂可以阻断AICD，并且这种AICD由TRAIL介导。这些结果表明，TRAIL可以是T细胞中AICD的介导剂。这些不同的外周血T细胞凋亡机制可能在HIV感染的发病机制中发挥不同的作用。
Apoptosis of peripheral blood T cells has been suggested to play an important role in the pathogenesis of human immunodeficiency virus (HIV) infection. Spontaneous, Fas (CD95)–induced and activation-induced T cell apoptosis have all been described in peripheral blood mononuclear cell cultures of HIV-infected individuals. We have previously shown that activation-induced T cell apoptosis is Fas independent in peripheral blood T cells from HIV+ individuals. In this study, we extend and confirm these observations by using an inhibitor of interleukin-1β converting enzyme (ICE) homologues. We show that z-VAD-fmk, a tripeptide inhibitor of ICE homologues, can inhibit Fas-induced apoptosis of peripheral blood CD4+ and CD8+ T cells from asymptomatic HIV+ individuals. z-VAD-fmk also inhibited activation (anti-CD3)– induced CD4+ and CD8+ T cell apoptosis (AICD) in some but not all asymptomatic HIV+ individuals. Apoptosis was measured by multiparameter flow cytometry. The z-VAD-fmk inhibitor also enhanced survival of T cells in anti-Fas or anti-CD3 antibody-treated cultures and inhibited DNA fragmentation. AICD that could be inhibited by z-VAD-fmk was Fas independent and could be inhibited with a blocking monoclonal antibody to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), a recently described member of the TNF/nerve growth factor ligand family. The above findings show that Fas-induced T cell apoptosis is ICE dependent in HIV infection. AICD can be blocked by ICE inhibitors in some patients, and this AICD is mediated by TRAIL. These results show that TRAIL can be a mediator of AICD in T cells. These different mechanisms of peripheral blood T cell apoptosis may play different roles in the pathogenesis of HIV infection.