Pou6f1 transcriptional control of memory CD8+ T cells

描述（由申请人提供）：为了保护我们免受病原体再次暴露，记忆淋巴细胞必须进行稳态自我更新，并保持对后续感染的反应。在CD8+ T细胞的情况下，一些拮抗转录因子对似乎调节了成为终末分化效应细胞或自我更新记忆细胞的初始决定。然而，目前尚不清楚这些转录因子本身是如何协调调节的，以及哪些遗传回路负责随后的记忆细胞自我更新。鉴于记忆淋巴细胞表现出许多通常与干细胞相关的功能属性，我们假设记忆淋巴细胞重新激活了造血干细胞遗传程序的一部分。为了支持这一观点，我们发表了记忆B细胞、记忆CD8+ T细胞和造血干细胞之间共有的共同转录特征。我们进一步确定了一种转录因子，Pou6f1，相对于寿命较短的细胞，它在记忆B和CD8+ T细胞中选择性上调。Pou6f1是转录因子家族的一员，是胚胎干细胞自我更新调节因子Pou5f1（又名Oct4）的类似物。我们认为，Pou6f1在记忆性CD8+ T细胞中的作用与Oct4在胚胎干细胞中的作用类似。该建议的中心假设是，Pou6f1通过建立和维持一个自我强化的遗传回路来协调多种转录因子和信号通路的表达，从而指导记忆CD8+ T细胞的自我更新。为了在体内验证这一假设，我们产生了表达Pou6f1的两个不同的floxed等位基因的小鼠，这将使我们能够测试Pou6f1的功能相关性，并确定Pou6f1在记忆CD8+ T细胞中的转录靶点。通过阐明记忆性CD8+ T细胞产生、功能和维持的核心遗传回路，该建议将为控制适应性免疫记忆的机制提供关键见解。

DESCRIPTION (provided by applicant): In order to protect us from pathogen reexposure, memory lymphocytes must undergo homeostatic self-renewal and remain poised to respond to subsequent infection. In the case of CD8+ T cells, several antagonistic pairs of transcription factors appear to regulate the initial decision to become a terminally differentiated effector cell or a self- renewing memory cell. However, it remains unclear how these transcription factors are themselves coordinately regulated, and further which genetic circuits are responsible for subsequent memory cell self-renewal. Given that memory lymphocytes exhibit many of the functional attributes typically associated with stem cells, we hypothesized that memory lymphocytes have reactivated a portion of the hematopoietic stem cell genetic program. In support of this idea, we published a common transcriptional signature shared between memory B cells, memory CD8+ T cells and hematopoietic stem cells. We further identified a transcription factor, Pou6f1, that is selectively upregulated in memory B and CD8+ T cells relative to shorter-lived cells. Pou6f1 is a member of the Pou-domain family of transcription factors and is a paralog of the embryonic stem cell self-renewal regulator Pou5f1 (aka Oct4). We believe Pou6f1 functions in memory CD8+ T cells in a manner similar to Oct4 in embryonic stem cells. The central hypothesis of this proposal is that Pou6f1 directs memory CD8+ T cell self-renewal by establishing and maintaining a self-reinforcing genetic circuit that coordinates the expression of multiple transcription factors and signaling pathways. In order to test this hypothesis in vivo, we have generated mice expressing two different floxed alleles of Pou6f1 that will allow us to test Pou6f1's functional relevance and identify Pou6f1's transcriptional targets in memory CD8+ T cells. By elucidating the core genetic circuitry responsible for memory CD8+ T cell generation, function and maintenance, this proposal will provide key insights into the mechanisms controlling adaptive immune memory. PUBLIC HEALTH RELEVANCE: Memory lymphocytes are responsible for long-lived immunity, driving immune responses that can be either life-saving (as in the case of vaccines) or life-threatening (as in the case of autoimmune diseases). Despite the importance of memory cells, there are no memory-specific therapies currently available. In the fullness of time, we anticipate that identification of the genetic circuitry of CD8+ T cell memory, its targets, and the upstream signaling network that drives it will provide potential therapeutic candidates that might be used to aid in the design of more efficacious therapeutic cancer vaccines.