Negative regulatory pathways in T cell quiescence and T cell response

描述（由申请人提供）：在转录水平，对与T细胞静止的主动维持相关的途径知之甚少。我们最近发现，细胞内在信号传导途径是维持成熟T细胞处于静止状态所必需的;如果这些途径被破坏，即使在没有抗原攻击的淋巴细胞充足的宿主中，静止T细胞也会异常激活（Nat Immunol 2011）。我们的长期目标是确定这样的调控基因和途径，积极抑制T细胞活化，并确定其在T细胞静止，T细胞稳态，并在初级和记忆T细胞反应的作用。在不久的将来，具体来说，我们正在研究与T细胞静止相关的途径如何影响T细胞活化的速率和程度，从而影响反应的动力学和大小以及效应和记忆T细胞分化。我们还将解决一个长期公认但知之甚少的过程，这是维持记忆T细胞的基础：强制记忆T细胞静止是长期记忆存活的重要机制吗？这些研究将提供基本信息和新的机制见解，以指导在广泛的临床环境中对T细胞静止与活化的治疗操作，包括自身免疫，传染病和疫苗开发。 最近，我们已经确定Foxp 1作为一个重要的转录调节维持静止的幼稚T细胞在稳态。在这个提议中，我们将确定Foxp 1蛋白在抗原诱导的T细胞反应中的作用，并阐明Foxp 1强制静止的机制。本研究的两个具体目的是：1）确定Foxp 1对T细胞激活和记忆的调节作用。我们已经产生了几个Foxp 1亚型特异性条件转基因小鼠以及Foxp 1诱导缺失小鼠模型。我们将利用这些新的获得和丧失功能的小鼠品系来阐明Foxp 1及其亚型在T细胞激活和记忆中的作用。2)阐明Foxp 1强制T细胞静止的分子机制。最近，我们建立了一个全基因组Foxp 1 ChIP测序分析，并确定了一些新的Foxp 1候选靶基因。我们将联合收割机候选和无偏见的全基因组方法来阐明Foxp 1通路如何负调控细胞生长/代谢和细胞周期进程，从而加强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Foxp 1靶点的独特见解，我们的研究具有高度意义，因为它有可能揭示几个新的和重要的分子， Foxp 1转录网络在调节T细胞静止、激活和记忆中的潜在机制。

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.