Rapid Evolution of the CD8+ TCR Repertoire in Neonatal Mice.
Rapid Evolution of the CD8+ TCR Repertoire in Neonatal Mice.
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DOI：
10.4049/jimmunol.1502126
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发表时间：
2016-03-15
期刊：
影响因子：
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通讯作者：
Katsikis PD
中科院分区：
文献类型：
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作者：
Carey AJ;Gracias DT;Thayer JL;Boesteanu AC;Kumova OK;Mueller YM;Hope JL;Fraietta JA;van Zessen DB;Katsikis PD
目前，对于研究新生儿急性感染和病毒特异性CD8+T细胞(CTL)反应的最合适的动物模型，几乎没有达成共识。对不同年龄的新生小鼠的幼稚CTL进行了TCRβ高通量测序，证实了Vβ家族基因的不同用途。使用急性流感感染模型，我们检测了感染A型流感病毒的新生和成年小鼠的CTL反应的TCR谱系。与7日龄和成年小鼠相比，3日龄小鼠的初级NP(366-374)特异性CTL反应显著降低，而次级CTL反应正常。对NP(36 6-3 74)特异性CTL TCR谱系的分析显示，在3天大的新生儿中，Vβ基因的使用不同，公共克隆型显著减少。这可能是这些新生儿CTL反应受损的基础。为了直接测试这一点，我们检查了控制TCR是否会恢复新生儿的CTL反应。我们进行了非转基因和TCR转基因的OVA(257-264)特异性(OT-I)CD8+T细胞过继转移到流感感染宿主中，结果显示幼稚的新生儿和成人OT-I细胞在新生儿和成年宿主中同样生长良好。相比之下，非转基因新生儿CD8+T细胞在转移到成人体内时无法扩增。我们进一步证明，TCR亲和力的差异可能有助于减少内源性新生儿CTL的扩张。这些研究强调了新生儿TCR谱系在出生后第一周的快速演变，并表明新生儿CTL免疫功能受损是由不成熟的TCR谱系引起的，而不是内在的信号缺陷或抑制环境。
Currently, there is little consensus regarding the most appropriate animal model to study acute infection and the virus–specific CD8+ T cell (CTL) responses in neonates. TCRβ high-throughput sequencing in naïve CTL of differently aged neonatal mice was performed, which demonstrated differential Vβ family gene usage. Using an acute influenza infection model, we examined the TCR repertoire of the CTL response in neonatal and adult mice infected with influenza type A virus. Three-day old mice mounted a greatly reduced primary NP(366–374)-specific CTL response when compared to 7-day old and adult mice, while secondary CTL responses were normal. Analysis of NP(366–374)-specific CTL TCR repertoire revealed different Vβ gene usage and greatly reduced public clonotypes in 3-day old neonates. This could underlie the impaired CTL response in these neonates. To directly test this, we examined whether controlling the TCR would restore neonatal CTL responses. We performed adoptive transfers of both non-transgenic and TCR-transgenic OVA(257–264)-specific (OT-I) CD8+ T cells into influenza-infected hosts, which revealed that naïve neonatal and adult OT-I cells expand equally well in neonatal and adult hosts. In contrast, non-transgenic neonatal CD8+ T cells when transferred into adults failed to expand. We further demonstrate that differences in TCR avidity may contribute to decreased expansion of the endogenous neonatal CTL. These studies highlight the rapid evolution of the neonatal TCR repertoire during the first week of life and show that impaired neonatal CTL immunity results from an immature TCR repertoire, rather than intrinsic signaling defects or a suppressive environment.