Institute for Virology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
Leibniz Institute of Virology (LIV), Hamburg, Germany.
PLoS Pathog. 2024 Aug 15;20(8):e1012173. doi: 10.1371/journal.ppat.1012173. eCollection 2024 Aug.
CD8 T cells are the predominant effector cells of adaptive immunity in preventing cytomegalovirus (CMV) multiple-organ disease caused by cytopathogenic tissue infection. The mechanism by which CMV-specific, naïve CD8 T cells become primed and clonally expand is of fundamental importance for our understanding of CMV immune control. For CD8 T-cell priming, two pathways have been identified: direct antigen presentation by infected professional antigen-presenting cells (pAPCs) and antigen cross-presentation by uninfected pAPCs that take up antigenic material derived from infected tissue cells. Studies in mouse models using murine CMV (mCMV) and precluding either pathway genetically or experimentally have shown that, in principle, both pathways can congruently generate the mouse MHC/H-2 class-I-determined epitope-specificity repertoire of the CD8 T-cell response. Recent studies, however, have shown that direct antigen presentation is the canonical pathway when both are accessible. This raised the question of why antigen cross-presentation is ineffective even under conditions of high virus replication thought to provide high amounts of antigenic material for feeding cross-presenting pAPCs. As delivery of antigenic material for cross-presentation is associated with programmed cell death, and as CMVs encode inhibitors of different cell death pathways, we pursued the idea that these inhibitors restrict antigen delivery and thus CD8 T-cell priming by cross-presentation. To test this hypothesis, we compared the CD8 T-cell responses to recombinant mCMVs lacking expression of the apoptosis-inhibiting protein M36 or the necroptosis-inhibiting protein M45 with responses to wild-type mCMV and revertant viruses expressing the respective cell death inhibitors. The data reveal that increased programmed cell death improves CD8 T-cell priming in mice capable of antigen cross-presentation but not in a mutant mouse strain unable to cross-present. These findings strongly support the conclusion that CMV cell death inhibitors restrict the priming of CD8 T cells by antigen cross-presentation.
CD8 T 细胞是适应性免疫的主要效应细胞，可预防细胞病变组织感染引起的巨细胞病毒（CMV）多器官疾病。CMV 特异性初始 CD8 T 细胞被激活并克隆扩增的机制对于我们理解 CMV 免疫控制至关重要。对于 CD8 T 细胞的初始激活，已经确定了两种途径：感染的专业抗原呈递细胞（pAPC）的直接抗原呈递和未感染的 pAPC 的抗原交叉呈递，后者摄取来自感染的组织细胞的抗原物质。使用小鼠巨细胞病毒（mCMV）并在遗传或实验上排除任何一种途径的小鼠模型研究表明，原则上，两种途径都可以一致地产生 CD8 T 细胞反应的 MHC/H-2 类决定表位特异性 repertoire。然而，最近的研究表明，当两种途径都可及时，直接抗原呈递是经典途径。这就提出了一个问题，即在被认为提供大量抗原物质供交叉呈递 pAPC 摄取的高病毒复制条件下，为什么抗原交叉呈递无效。由于抗原呈递与程序性细胞死亡有关，并且 CMV 编码不同细胞死亡途径的抑制剂，我们探讨了这些抑制剂是否会限制抗原的呈递，从而限制交叉呈递的 CD8 T 细胞的初始激活。为了验证这一假设，我们比较了缺乏凋亡抑制蛋白 M36 或坏死抑制蛋白 M45 表达的重组 mCMV 与野生型 mCMV 和表达相应细胞死亡抑制剂的回复病毒引起的 CD8 T 细胞反应。数据表明，程序性细胞死亡的增加可改善能够进行抗原交叉呈递的小鼠的 CD8 T 细胞初始激活，但不能改善无法进行抗原交叉呈递的突变小鼠品系。这些发现强烈支持这样的结论，即 CMV 细胞死亡抑制剂限制了抗原交叉呈递的 CD8 T 细胞的初始激活。
