Transcriptional regulation of T cell quiescience and activation

描述(申请人提供)：外周幼稚T淋巴细胞的静止状态被认为是由于缺乏激活信号所致。然而，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，而在转录水平上对此知之甚少。Forkhead box(Fox)蛋白是一个转录因子大家族，在发育、衰老和癌症中具有不同的功能。最近我们发现转录因子Foxp1对幼稚T细胞的静止起着重要的细胞内源性调节作用，这为成熟T细胞的静止被积极地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中起重要作用。 T细胞活化。在这个方案中，我们将结合不同的方法来确定Foxp1调控T细胞静止的功能靶点和分子途径，并确定Foxp1在体内抗原诱导的T细胞激活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，这些策略将操纵T细胞的激活状态来治疗自身免疫和传染病，并有助于疫苗的开发。

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.