Neonatal CD8 T-cell hierarchy is distinct from adults and is influenced by intrinsic T cell properties in respiratory syncytial virus infected mice.
Neonatal CD8 T-cell hierarchy is distinct from adults and is influenced by intrinsic T cell properties in respiratory syncytial virus infected mice.
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新生儿CD8 T细胞层次结构与成年人不同，受呼吸道合胞病毒感染小鼠的内在T细胞特性的影响。
DOI：
10.1371/journal.ppat.1002377
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发表时间：
2011-12
期刊：
影响因子：
6.7
通讯作者：
Graham BS
中科院分区：
文献类型：
--
作者：
Ruckwardt TJ;Malloy AM;Gostick E;Price DA;Dash P;McClaren JL;Thomas PG;Graham BS
在呼吸道合胞病毒感染成年CB6F1杂交小鼠后，建立了可预测的CD8 + T细胞表位层次，对来自M2蛋白的Kd限制性肽（SYIGSINNI）具有强烈的显性应答。对KdM282 - 90的应答是对M蛋白亚显性表位（NAITNAKII，DbM187 - 195）的应答的105倍。新生小鼠感染后，出现了一个明显不同的表位层次，共显性响应KdM282 - 90和DbM187 - 195。在感染前，幼稚的CD8 + T细胞从成人连续转移到同类新生儿中，表明内在的CD8 + T细胞因子有助于年龄相关的层次差异。表位特异性前体频率在成人和新生儿之间不同，并影响，但不能预测感染后的层次结构。此外，KdM282 - 90特异性细胞的优势与TdT活性无关。新生小鼠中表位特异性V β库的使用更受限制，功能亲合力更低。新生儿模式的共显性感染后的变化，在10天的年龄，并迅速转移到成人模式的极端KdM282 - 90-优势。因此，T细胞的功能特性被发育因子以表位特异性和年龄依赖性的方式选择性地修饰。RSV每年都会导致冬季呼吸道疾病流行，住院率在2.5个月大时达到峰值。病毒感染细胞的清除依赖于CD8 T细胞，确定CD8 T细胞调节机制对于理解RSV疾病发病机制和指导治疗干预至关重要。CD8 T细胞通过检测从宿主细胞MHC分子中呈递的病毒蛋白质裂解的肽来识别病毒感染的细胞。CD8 T细胞对来自病毒的经加工的肽表位的应答强度通常假定可预测的应答层次。在具有H-2b和H-2d MHC等位基因的成年杂交小鼠中，大多数CD8 T细胞应答靶向来自M2蛋白的肽并由Kd MHC分子KdM282 - 90呈递，并且较小的CD8 T细胞亚群应答来自M蛋白的肽DbM187 - 195。有趣的是，当感染新生杂交小鼠时，未观察到显性模式，DbM187 - 195应答等于或大于KdM282 - 90应答。我们发现，成人的优势模式出现在10天的年龄和T细胞的表位特异性和年龄依赖性的方式修改的发育因子。这些观察结果可能会影响未来的疫苗设计。
Following respiratory syncytial virus infection of adult CB6F1 hybrid mice, a predictable CD8+ T cell epitope hierarchy is established with a strongly dominant response to a Kd-restricted peptide (SYIGSINNI) from the M2 protein. The response to KdM282-90 is ∼5-fold higher than the response to a subdominant epitope from the M protein (NAITNAKII, DbM187-195). After infection of neonatal mice, a distinctly different epitope hierarchy emerges with codominant responses to KdM282-90 and DbM187-195. Adoptive transfer of naïve CD8+ T cells from adults into congenic neonates prior to infection indicates that intrinsic CD8+ T cell factors contribute to age-related differences in hierarchy. Epitope-specific precursor frequency differs between adults and neonates and influences, but does not predict the hierarchy following infection. Additionally, dominance of KdM282-90 –specific cells does not correlate with TdT activity. Epitope-specific Vβ repertoire usage is more restricted and functional avidity is lower in neonatal mice. The neonatal pattern of codominance changes after infection at 10 days of age, and rapidly shifts to the adult pattern of extreme KdM282- 90 -dominance. Thus, the functional properties of T cells are selectively modified by developmental factors in an epitope-specific and age-dependent manner. RSV causes yearly winter epidemics of respiratory disease with peak hospitalization rates at 2.5 months of age. Clearance of virus-infected cells depends on CD8 T-cells, and defining mechanisms of CD8 T-cell regulation is essential for understanding RSV disease pathogenesis and guiding therapeutic interventions. CD8 T-cells recognize a virus-infected cell by detecting peptides cleaved from viral proteins that are presented in host cell MHC molecules. The strength of CD8 T-cell response to processed peptide epitopes from the virus commonly assumes a predictable response hierarchy. In adult hybrid mice that have both H-2b and H-2d MHC alleles, the majority of the CD8 T-cell response is targeted at a peptide from the M2 protein and presented by the Kd MHC molecule, KdM282-90, and a smaller subset of CD8 T-cells respond to a peptide from the M protein, DbM187-195. Interestingly, when infecting neonatal hybrid mice the dominance pattern is not seen and the DbM187-195 response is equal to or greater than the KdM282-90 response. We show that the adult dominance pattern emerges at 10 days of age and that T cells are modified by developmental factors in an epitope-specific and age-dependent manner. These observations may influence future vaccine design.
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