The Neonatal CD8+ T Cell Repertoire Rapidly Diversifies during Persistent Viral Infection.
The Neonatal CD8+ T Cell Repertoire Rapidly Diversifies during Persistent Viral Infection.
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DOI：
10.4049/jimmunol.1501867
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发表时间：
2016-02-15
期刊：
影响因子：
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通讯作者：
Rudd BD
中科院分区：
文献类型：
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作者：
Venturi V;Nzingha K;Amos TG;Charles WC;Dekhtiarenko I;Cicin-Sain L;Davenport MP;Rudd BD
巨细胞病毒（CMV）是美国最常见的先天性感染。先天性巨细胞病毒的主要靶点是大脑，临床表现包括智力低下、视力障碍和感音神经性听力损失。先前的报告表明，需要CD8+ T细胞来控制病毒复制，并且即使在初始感染被清除后，大脑中仍存在大量cmv特异性CD8+ T细胞。然而，CD8+ T细胞在脑潜伏期间的动态仍未明确。在本报告中，我们使用T细胞受体（TCR）测序来跟踪慢性感染期间小鼠脑和脾脏中新生儿克隆型的发展和维持。鉴于组织常驻记忆CD8+ T细胞的不连续性质，我们假设新生儿TCR克隆型将被“锁定”在大脑中并持续到成年。令人惊讶的是，我们发现新生儿感染小鼠的抗原特异性T细胞库在大脑和脾脏的持续感染期间多样化，而在早期和晚期感染中，大脑和脾脏的CD8+ T细胞群保持了实质性的相似性。然而，尽管脾脏和大脑抗原特异性T细胞库存在多样化和潜在的交换，但我们观察到，新生儿感染的特征——种系编码的TCR克隆型在大脑中持续存在，尽管有时丰度较低。这些结果为新生儿巨细胞病毒感染后CD8+ T细胞谱的进化提供了有价值的见解，因此对开发早期控制巨细胞病毒的治疗策略具有重要意义。
Cytomegalovirus (CMV) is the most common congenital infection in the United States. The major target of congenital CMV is the brain, with clinical manifestations including mental retardation, vision impairment and sensorineural hearing loss. Previous reports have shown that CD8+ T cells are required to control viral replication and significant numbers of CMV-specific CD8+ T cells persist in the brain even after the initial infection has been cleared. However, the dynamics of CD8+ T cells in the brain during latency remains largely undefined. In this report, we used T cell receptor (TCR) sequencing to track the development and maintenance of neonatal clonotypes in the brain and spleen of mice during chronic infection. Given the discontinuous nature of tissue resident memory CD8+ T cells, we hypothesized that neonatal TCR clonotypes would be ‘locked-in’ the brain and persist into adulthood. Surprisingly, we found that the antigen-specific T cell repertoire in neonatal-infected mice diversified during persistent infection in both the brain and spleen, while maintaining substantial similarity between the CD8+ T cell populations in the brain and spleen in both early and late infection. However, despite the diversification of, and potential interchange between, the spleen and brain antigen-specific T cell repertoires, we observed that germline-encoded TCR clonotypes, characteristic of neonatal infection, persisted in the brain, albeit sometimes in low abundance. These results provide valuable insights into the evolution of CD8+ T cell repertoires following neonatal CMV infection and thus have important implications for the development of therapeutic strategies to control CMV in early life.