Clonotype Selection and Composition of Human CD8 T Cells Specific for Persistent Herpes Viruses Varies with Differentiation but Is Stable Over Time
Clonotype Selection and Composition of Human CD8 T Cells Specific for Persistent Herpes Viruses Varies with Differentiation but Is Stable Over Time
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DOI：
10.4049/jimmunol.0803647
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发表时间：
2009-07-01
影响因子：
4.4
通讯作者：
Rufer, Nathalie
中科院分区：
文献类型：
--
作者：
Iancu, Emanuela M.;Corthesy, Patricia;Rufer, Nathalie
持续性疱疹病毒感染的再活化保护是由Ag特异性CD 8 T细胞应答介导的，其受到仍然知之甚少的机制的高度调节。在这项研究中，我们分析了分化和克隆型动力学的EBV和CMV特异性T细胞从健康成人。尽管这些T淋巴细胞包括从早期分化（EM/CD 28（pos））到晚期分化（EMRA/CD 28（neg））阶段的所有亚群，但它们在这些亚群的大小/比例上不同。深入的克隆组成分析揭示了TCR库，这是高度限制的CMV-和相对多样化的EBV特异性细胞。几乎所有在EMRA/CD 28（阴性）亚群中鉴定的病毒特异性克隆型也在分化程度较低的“记忆”细胞库中发现。然而，显着的差异，在这些亚群中观察到的优势模式，因为一些克隆型选择分化，而其他人没有。晚分化CMV特异性克隆型的主要特征是TCR对CD 8辅助受体相互作用的依赖性较低。然而，所有的克隆型表现出类似的功能亲合力，表明CD 8在较低的TCR亲合力的克隆型的补偿作用。重要的是，克隆型选择和组成的每个病毒特异性子集分化后高度保存随着时间的推移，在特定的分化阶段在4年内的一段时间内存在相同的优势克隆型。值得注意的是，克隆型分布是稳定的，不仅在晚分化，但也在分化较低的T细胞亚群。因此，T细胞克隆型随着分化而分离，但克隆组成一旦建立就保持恒定至少几年。这些发现揭示了健康成人中稳态保护性T细胞活性的高度复杂控制的新特征。免疫学杂志，2009，183：319-331.
Protection from reactivation of persistent herpes virus infection is mediated by Ag-specific CD8 T cell responses, which are highly regulated by still poorly understood mechanisms. In this study, we analyzed differentiation and clonotypic dynamics of EBV- and CMV-specific T cells from healthy adults. Although these T lymphocytes included all subsets, from early-differentiated (EM/CD28(pos)) to late-differentiated (EMRA/CD28(neg)) stages, they varied in the sizes/proportions of these subsets. In-depth clonal composition analyses revealed TCR repertoires, which were highly restricted for CMV- and relatively diverse for EBV-specific cells. Virtually all virus-specific clonotypes identified in the EMRA/CD28(neg) subset were also found within the pool of less differentiated "memory" cells. However, striking differences in the patterns of dominance were observed among these subsets, because some clonotypes were selected with differentiation while others were not. Late-differentiated CMV-specific clonotypes were mostly characterized by TCR with lower dependency on CD8 coreceptor interaction. Yet all clonotypes displayed similar functional avidities, suggesting a compensatory role of CD8 in the clonotypes of lower TCR avidity. Importantly, clonotype selection and composition of each virus-specific subset upon differentiation was highly preserved over time, with the presence of the same dominant clonotypes at specific differentiation stages within a period of 4 years. Remarkably, clonotypic distribution was stable not only in late-differentiated but also in less-differentiated T cell subsets. Thus, T cell clonotypes segregate with differentiation, but the clonal composition once established is kept constant for at least several years. These findings reveal novel features of the highly sophisticated control of steady state protective T cell activity in healthy adults. The Journal of Immunology, 2009, 183: 319-331.