Transcriptional regulation of T cell quiescence and activation

描述（由申请人提供）：认为外周初始T淋巴细胞的静止状态是由于缺乏激活信号。然而，最近的研究表明，T细胞静止不是默认的，而是由细胞外在和内在机制积极维持的，关于这一点在转录水平上知之甚少。叉头盒（FOX）蛋白包括在发育、衰老和癌症中具有不同功能的转录因子大家族。最近，我们发现转录因子Foxp1对幼稚T细胞的静止发挥重要的细胞内在调节作用，这为成熟T细胞的静止被积极维持提供了直接证据。同时，我们新的初步研究也开始揭示Foxp1转录网络在激动剂诱导的细胞凋亡中起重要作用。 T细胞活化。在本研究中，我们将联合收割机的各种方法来确定Foxp1在控制T细胞静止中的功能靶点和分子通路，并确定Foxp1在抗原诱导的T细胞活化和反应中的关键作用。 从这些研究中获得的知识将为设计新的治疗策略提供信息，这些治疗策略将操纵T细胞活化状态以治疗自身免疫性和感染性疾病，并有助于疫苗开发。 公共卫生相关性：最近的研究表明，T细胞静止不是默认的，而是通过细胞外在和内在机制积极维持的，关于这一点， 在分子水平上是已知的。了解T细胞静止的转录调控的关键因素的研究将提供机制的见解，以指导设计新的治疗策略，将操纵T细胞活化状态用于治疗自身免疫性和感染性疾病，并有助于疫苗开发。

DESCRIPTION (provided by applicant): The quiescent state of peripheral naive T lymphocytes was thought to be due to the lack of activation signals. Recent studies, however, 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 transcriptional level. Forkhead box (FOX) proteins comprise a large family of transcription factors with diverse functions in development, aging and cancer. Recently we discovered that transcription factor Foxp1 exerts essential cell-intrinsic regulation of the quiescence of naive T cells, providing direct evidence that mature T cell quiescence is actively maintained. Meanwhile, our new preliminary studies also start to reveal that Foxp1 transcriptional network plays an important role in agonist- induced T cell activation. In this proposal, we will combine various approaches to identify functional targets and molecular pathways regulated by Foxp1 in controlling T cell quiescence, and to define the critical roles of Foxp1 in antigen-induced T cell activation and responses in vivo. Knowledge obtained from these studies will provide information for the design of new therapeutic strategies that would manipulate T cell activation status for the treatment of autoimmune and infectious diseases, and aid in vaccine development. PUBLIC HEALTH RELEVANCE: 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 mechanistic insights to guide the design of new therapeutic strategies that would manipulate T cell activation status for the treatment of autoimmune and infectious diseases, and aid in vaccine development.