Regulation of neonatal immunity by let-7/Lin28

描述(申请人提供)：新生儿对细胞内病原体高度敏感，对感染的免疫力较差。由于对这些感染因子的免疫在很大程度上依赖于记忆性CD8+T细胞，我们对早期生命中CD8+T细胞的反应进行了详细的分析，发现新生儿CD8+T细胞在分化为记忆性CD8+T细胞方面存在先天缺陷。令人惊讶的是，新生儿CD8+T细胞的记忆形成障碍并不是由于无法反应，而是新生儿CD8+T细胞比成人细胞增殖更快，并迅速分化为终末分化。Let-7miRNA家族是发育早期最古老、最保守的增殖和分化调节因子之一。Let-7通过靶向多种代谢基因、细胞周期因子和癌基因抑制细胞的增殖和生长。虽然let-7在成人CD8+T细胞中高水平表达，但它在新生儿CD8+T细胞中的表达被Lin28b阻断，创造了一个非常有利于快速增殖的基因组图谱。因此，我们认为，新生儿CD8+T细胞变得更加终末分化，形成较差的记忆细胞，因为无法通过let-7抑制主要的转录和代谢途径。我们的建议将检验这一假设，即不同的遗传程序，由let-7/Lin28b轴调节，改变新生儿感染后记忆CD8+T细胞的产生和维持。在第一个目标(SA1)中，我们将调节不同年龄的CD8+T细胞中let7和Lin28b的表达水平，并确定它们在新生儿和成人记忆CD8+T细胞形成中的作用。在后两个AIMS(SA2和SA3)中，我们将确定LET-7/Lin28b调控的关键转录因子和代谢途径，这些转录因子和代谢通路与早期记忆CD8+T细胞的发育受损有关。这项工作完成后，我们将获得一个完整的机制了解为什么新生儿CD8+T细胞无法分化为记忆，并知道纠正转录和代谢差异是否可以恢复早期生命的保护性免疫。我们的重点放在let-7/Lin28b上，它似乎调节了这些差异，这将允许我们操纵以特定方式产生的记忆CD8+T细胞的数量和类型。这是一种新的、有针对性的方法，可以促进记忆T细胞的早期发育。

DESCRIPTION (provided by applicant): Neonates are highly susceptible to intracellular pathogens and develop poor immunity to infection. Since immunity against these infectious agents is largely dependent upon memory CD8+ T cells, we have performed detailed analysis of the CD8+ T cell response in early life and found that neonatal CD8+ T cells are intrinsically defective at differentiating into memory CD8+ T cells. Surprisingly, impaired memory formation by neonatal CD8+ T cells was not due to an inability to respond, rather neonatal CD8+ T cells proliferated more rapidly than adult cells and quickly became terminally differentiated. One of the most ancient and conserved regulators of proliferation and differentiation during early stages of development is the let-7 miRNA family. Let- 7 represses cell proliferation and growth by targeting many metabolic genes, cell cycle factors and oncogenes for repression. While let-7 is expressed at high levels in adult CD8+ T cells, its expression is blocked by Lin28b in neonatal CD8+ T cells, creating a genomic landscape that is highly conducive for rapid proliferation. Therefore, we believe that neonatal CD8+ T cells become more terminally differentiated and form poor memory cells, because of an inability to repress major transcriptional and metabolic pathways via let-7. Our proposal will test the hypothesis that different genetic programs, regulated by the let-7/Lin28b axis, alter the generation and maintenance of memory CD8+ T cells following neonatal infection. In the first aim (SA1), we will adjust expression levels of let7 and Lin28b in different aged CD8+ T cells and determine their role in neonatal and adult memory CD8+ T cell formation. In the last 2 aims (SA2 and SA3), we will identify the key transcription factors and metabolic pathways that are regulated by let-7/Lin28b and contributing to impaired development of memory CD8+ T cells in early life. Upon completion of this work, we will have obtained a complete mechanistic understanding of why neonatal CD8+ T cells fail to differentiate into memory and know whether correcting transcriptional and metabolic differences can restore protective immunity in early life. Our focus on let-7/Lin28b, which appears to regulate these differences, will allow us to manipulate the number and type of memory CD8+ T cells that are generated in specific ways. This is a novel and targeted approach to enhance memory T cell development in early life.