Pou6f1 transcriptional control of memory CD8+ T cells

Pou6f1 记忆 CD8 T 细胞的转录控制

基本信息

批准号：
8164939
负责人：
CHANCE MARION JOHN LUCKEY
金额：
$ 24.44万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8164939
关键词：
Address Alleles Autoimmune Diseases Automobile Driving B-Lymphocytes Bacterial Infections Biochemical CD8-Positive T-Lymphocytes CD8B1 gene Cancer Vaccines Cells Effector Cell Exhibits Family Generations Genes Genetic Genetic Programming Genetic Transcription Hematopoietic stem cells Immune Immune response Immunity Infection Interleukin-15 Interleukin-7 Lead Life Listeria monocytogenes Lymphocyte Maintenance Mature Lymphocyte Memory Memory B-Lymphocyte Mus Population Proliferating Proto-Oncogene Proteins c-akt Publishing Relative (related person)Reserve Stem Cell Role Series Signal Pathway Signal Transduction Stem cells T memory cell T-Lymphocyte Tamoxifen Testing Therapeutic Transcriptional Regulation Vaccines Vaccinia virus Virus Diseases design embryonic stem cell granzyme B human FRAP1 protein in vivo insight member paralogous gene pathogen promoter recombinase research study response self-renewal transcription factor

项目摘要

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.

描述（由申请人提供）：为了保护我们免受病原体的侵害，记忆淋巴细胞必须进行体内稳态自我更新，并准备对随后的感染做出反应。在CD8+ T细胞的情况下，几种转录因子的拮抗对似乎调节了最初的决定，以成为末端分化的效应细胞或自我更新记忆细胞。但是，尚不清楚这些转录因子本身如何协调调节，进一步的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通常与干细胞相关的许多功能属性，我们假设记忆淋巴细胞已重新激活了造血干细胞遗传程序的一部分。为了支持这一想法，我们在记忆B细胞，内存CD8+ T细胞和造血干细胞之间发表了共有的共有转录特征。我们进一步确定了一个转录因子POU6F1，该因子在记忆B和CD8+ T细胞中相对于较短的细胞有选择地上调。 POU6F1是转录因子的POU-域家族的成员，是胚胎干细胞自我更新调节剂POU5F1（aka oct4）的副产品。我们认为，POU6F1在胚胎干细胞中类似于OCT4的方式中在记忆CD8+ T细胞中起作用。该提案的中心假设是，POU6F1通过建立和维持自我强化的遗传回路来指导记忆CD8+ T细胞自我更新，从而协调多个转录因子和信号传导途径的表达。为了在体内检验这一假设，我们已经生成了表达POU6F1的两个不同的等位基因的小鼠，这将使我们能够测试POU6F1的功能相关性，并在存储器CD8+ T细胞中识别POU6F1的转录目标。通过阐明负责存储器CD8+ T细胞生成，功能和维护的核心遗传回路，该建议将为控制适应性免疫记忆的机制提供关键的见解。公共卫生相关性：记忆淋巴细胞负责长寿命的免疫力，推动可以挽救生命的免疫反应（如疫苗）或威胁生命（如自身免疫性疾病）。尽管记忆细胞很重要，但目前尚无记忆特异性疗法。在时间的填补度中，我们预计CD8+ T细胞记忆的遗传回路，其靶标和上游信号网络的鉴定，它将提供潜在的治疗候选者，这些候选可能可用于设计更有效的治疗癌症疫苗。