Negative regulatory pathways in T cell quiescence and T cell response

描述(由申请人提供)：在转录水平上，与主动维持T细胞静止有关的通路知之甚少。我们最近发现，细胞内的信号通路是维持成熟T细胞处于静止状态所必需的；如果这些通路被破坏，即使在淋巴充足的宿主中，在没有抗原挑战的情况下，静止的T细胞也会变得异常激活(NAT免疫学2011)。我们的长期目标是确定这些主动抑制T细胞激活的调控基因和途径，并确定它们在T细胞静止、T细胞稳态以及在原发和记忆T细胞反应中的作用。在不久的将来，具体地说，我们正在研究与T细胞静止相关的途径如何影响T细胞激活的速度和程度，从而影响反应、效应器和记忆性T细胞分化的动力学和幅度。我们还将讨论一个长期被认识但知之甚少的过程，这个过程是维持记忆T细胞的基础：强制记忆T细胞静止是否是长期记忆存活的基本机制？这些研究将提供基本信息和新的机制见解，以指导在包括自身免疫、传染病和疫苗开发在内的广泛临床环境中T细胞静止和激活的治疗操作。最近，我们发现Foxp1是维持幼稚T细胞在动态平衡过程中静止的重要转录调节因子。在这个方案中，我们将确定Foxp1蛋白在抗原诱导的T细胞反应中的作用，并阐明Foxp1执行静止的机制。两个具体目的是：1)确定Foxp1对T细胞激活和记忆的调节。我们已经建立了几个Foxp1亚型特异性的条件转基因小鼠，以及一个Foxp1可诱导缺失的小鼠模型。我们将利用这些新的功能获得和功能丧失的小鼠品系来阐明Foxp1及其亚型在T细胞激活和记忆中的作用。2)阐明Foxp1促进T细胞静止的分子机制。最近，我们建立了一种全基因组的Foxp1芯片测序方法，并鉴定了一些新的Foxp1候选靶基因。我们将结合候选和无偏见的全基因组方法来阐明Foxp1通路如何负向调节细胞生长/代谢和细胞周期进程，从而强制T细胞静止。基于我们建立的独特的小鼠品系和模型系统，以及对Foxp1靶点的独特见解，我们的研究具有非常重要的意义，因为它有可能揭示几个新的和重要的分子 Foxp1转录网络调控T细胞静止、激活和记忆的机制。 公共卫生相关性：公共卫生相关性声明最近的研究表明，T细胞的静止不是默认的，而是由细胞外在和内在机制积极维持的，在分子水平上对此知之甚少。了解关键因子对T细胞静止的转录调控机制的研究将为设计在包括自身免疫、传染病和疫苗开发在内的广泛临床环境中操纵T细胞静止和激活的策略提供基础信息。

DESCRIPTION (provided by applicant): At the transcriptional level, little is known about the pathways that are associated with the active maintenance of T cell quiescence. We recently showed that cell-intrinsic signaling pathways are required to maintain mature T cells in a quiescent state; if these pathways are disrupted, resting T cells become aberrantly activated even in lympho-replete hosts in the absence of antigen challenge (Nat Immunol 2011). Our long-term goals are to identify such regulatory genes and pathways that actively restrain T cel activation, and to define their roles in T cell quiescence, T cell homeostasis, and in primary and memory T cell responses. In the immediate future, specifically, we are asking how the pathways associated with T cell quiescence impact the rate and extent of T cell activation, thereby affecting the kinetics and magnitude of the response and effector and memory T cell differentiation. We will also address a long-recognized but poorly understood process that is fundamental to the maintenance of memory T cells: is enforcing memory T cell quiescence an essential mechanism for long-term memory survival? The studies will provide fundamental information and new mechanistic insights to guide therapeutic manipulation of T cell quiescence versus activation in a broad range of clinical settings including autoimmunity, infectious diseases, and vaccine development. Recently we have identified Foxp1 as an essential transcription regulator for maintaining the quiescence of naive T cells during homeostasis. In this proposal, we will determine the role of Foxp1 proteins in the antigen-induced T cell response and elucidate the mechanisms whereby Foxp1 enforces quiescence. The two specific aims are: 1) Determine the regulation of Foxp1 on T cel activation and memory. We have generated several Foxp1 isoform-specific conditional transgenic mice as well as a Foxp1 inducible deletion mouse model. We will utilize these novel gain- and loss-of-function mouse lines to elucidate the role of Foxp1 and its isoforms in T cel activation and memory. 2) Elucidate the molecular mechanisms by which Foxp1 enforces T cell quiescence. Recently we have established a genome-wide Foxp1 ChIP-sequencing assay and identified a number of novel Foxp1-candidate target genes. We will combine both candidate and unbiased genome-wide approaches to elucidate how the Foxp1 pathway negatively regulates cell growth/metabolism and cell cycle progression, thereby enforcing T cell quiescence. Based on the unique mouse lines and model systems that we have established and the unique insights of Foxp1 targets, our study is highly significant as it has the potential to reveal several novel and important molecular mechanisms underlying the transcriptional network of Foxp1 in regulating T cell quiescence, activation and memory. PUBLIC HEALTH RELEVANCE: Public Health Relevance Statement Recent studies have shown that T cell quiescence is not by default but actively maintained by both cell extrinsic and intrinsic mechanisms, about which little is known at the molecular level. The research on understanding the transcriptional regulation of T cell quiescence by key factors will provide fundamental information for devising strategies to manipulate T cell quiescence and activation in a wide range of clinical settings including autoimmunity, infectious diseases, and vaccine development.