Control of Lymphocyte Homeostasis by Foxo Transcription Factors

主要研究者/项目负责人（最后、第一、中间）：赫德里克、斯蒂芬M. 1 R01 AI073885-01A2 项目总结/摘要 造血细胞不断地更新。它们的分裂和死亡率决定了细胞的稳态数量和淋巴器官的大小。特别是，T淋巴细胞保持在一种活跃的静止状态，这种静止状态可以被缓解，以允许与感染相关的急剧扩张和收缩。目前尚不清楚主动静止、稳态、抗原介导的扩增调节和耐受之间是否存在联系。在这个提议中要测试的假设是，T细胞生理学的一些或所有这些方面都受到已知整合多种输入的转录因子家族的重要调控：生长因子，营养素和压力。这个家族被称为FOXO，第二个0表示由5个序列相关的成员组成的19个亚家族之一。我们发现Foxo 1和Foxo 3分别在T细胞和树突状细胞中介导重要的调节功能。在本申请中描述的实验被设计为理解导致这种调节的机制，并确定Foxo因子如何调节淋巴细胞增殖、存活、自身免疫性疾病和自身耐受。

Principal Investigator/Program Director (Last, first, middle): Hedrick, Stephen M. 1 R01 AI073885-01A2 PROJECT SUMMARY/ABSTRACT Hematopoietic cells constantly turn over. Their rates of division and death determine the steady-state number of cells and size of lymphoid organs. In particular, T lymphocytes are held in a state of active quiescence that can be relieved to allow for dramatic expansions and contractions associated with infection. Whether there is a connection between active quiescence, homeostasis, regulation of antigen-mediated expansion and tolerance is presently lmknown. The hypothesis to be tested in this proposal is that some or all of these aspects of T cell physiology are importantly regulated by a family of transcription factors known to integrate multiple inputs: growth factors, nutrients, and stress. This family has been termed FOXO for Forkhead bOX with the second 0 denoting one of 19 subfamilies consisting of five members related by sequence. We find that Foxo1 and Foxo3 mediate important regulatory functions in T cells and dendritic cells, respectively. The experiments described in this application are designed to lmderstand the mechanisms lmderlying this regulation, and determine how Foxo factors regulate lymphoproliferation, survival, autoimmune disease, and self-tolerance.