Bystander activation of cytotoxic T cells: studies on the mechanism and evaluation of in vivo significance in a transgenic mouse model.
Bystander activation of cytotoxic T cells: studies on the mechanism and evaluation of in vivo significance in a transgenic mouse model.
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DOI：
10.1084/jem.185.7.1241
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发表时间：
1997-04-07
影响因子：
15.3
通讯作者：
Zinkernagel, R M
中科院分区：
文献类型：
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作者：
Ehl, S;Hombach, J;Aichele, P;Hengartner, H;Zinkernagel, R M
旁观者激活，即在针对抗原 Y 的免疫反应期间，对抗原 X 具有特异性的 T 细胞的激活可能在病毒感染期间发生。然而，旁观者激活 T 细胞的频率较低，因此很难确定这种非特异性激活的机制和可能的体内相关性。本研究使用表达主要组织相容性复合体 I 类限制性 TCR 的转基因小鼠来克服这一限制，该 TCR 对淋巴细胞脉络丛脑膜炎病毒 (LCMV) 的糖蛋白肽 33-41 具有特异性。来自无特定病原体、未免疫的“初始”TCR 转基因小鼠的 CD8+ T 细胞在体内感染牛痘病毒或单核细胞增生李斯特菌或体外混合淋巴细胞培养期间，可以分化为 LCMV 特异性溶细胞效应 CTL。我们表明，在这些模型情况下（a）非特异性激活的 CTL 能够在体内提供抗病毒保护，（b）旁观者激活很大程度上独立于不同特异性的第二个 T 细胞受体的表达，（c）旁观者激活不是由广泛交叉反应的 TCR 介导，而是由细胞因子介导，（d）旁观者激活可以由细胞因子介导，例如 IL-2，但体外不是 α/β-IFN； (e) 总体而言，旁观者激活是一种罕见事件，在 TCR 转基因小鼠感染痘苗病毒期间，大约有二百分之一的 LCMV 特异性 CTL 发生在体内； (f) 在测试条件下，旁观者激活对非转基因CTL记忆没有显着的功能影响； (g)即使在TCR转基因情况下，存在非生理性大量的单一特异性T细胞，旁观者激活也不足以在糖尿病转基因小鼠模型中引起临床上明显的自身免疫性疾病。我们的结论是，尽管旁观者通过细胞因子激活可能会从初始前体中产生具有细胞溶解活性的 CTL，但定量考虑表明这通常不会产生重大的生物学后果。
Bystander activation, i.e., activation of T cells specific for an antigen X during an immune response against antigen Y may occur during viral infections. However, the low frequency of bystander-activated T cells has rendered it difficult to define the mechanisms and possible in vivo relevance of this nonspecific activation. This study uses transgenic mice expressing a major histocompatibility complex class I–restricted TCR specific for glycoprotein peptide 33-41 of lymphocytic choriomeningitis virus (LCMV) to overcome this limitation. CD8+ T cells from specific pathogen-free maintained, unimmunized “naive” TCR transgenic mice can differentiate into LCMV-specific cytolytic effector CTL during infections with vaccinia virus or Listeria monocytogenes in vivo or mixed lymphocyte culture in vitro. We show that in these model situations (a) nonspecifically activated CTL are able to confer antiviral protection in vivo, (b) bystander activation is largely independent of the expression of a second T cell receptor of different specificity, (c) bystander activation is not mediated by a broadly cross-reactive TCR, but rather by cytokines, (d) bystander activation can be mediated by cytokines such as IL-2, but not α/β-IFN in vitro; (e) bystander activation is, overall, a rare event, occuring in vivo in roughly 1 in 200 of the LCMV-specific CTL during infection of TCR transgenic mice with vaccinia virus; (f) bystander activation does not have a significant functional impact on nontransgenic CTL memory under the conditions tested; and (g) even in the TCR transgenic situation, where unphysiologically high numbers of T cells of a single specificity are present, bystander activation is not sufficient to cause clinically manifest autoimmune disease in a transgenic mouse model of diabetes. We conclude that although bystander activation via cytokines may generate cytolytically active CTL from naive precursors, quantitative considerations suggest that this is usually not of major biological consequence.