Naive T cell homeostasis: Treg selection and survival

外周耐受机制和免疫调节是防止潜在损害的必要条件 由逃避胸腺耐受诱导的自身反应性T细胞引起。其中，Treg细胞表达 FoxP 3转录因子是最好的特征，它们具有抑制免疫和 自身免疫反应，以及它们对人类治疗的令人兴奋的潜力。它们代表着一个恒定的比例 CD 4+细胞在特定个体的淋巴器官中的分布，但在一个物种中个体之间差异显著。 除了IL 2和TGF β的已知作用之外，控制选择和生长的机制和遗传变异也在研究中。 Treg库的稳态平衡仍不清楚。以下是关于存活和体内平衡的研究， 在前一个周期中，我们发现了“常规”T细胞，我们建议建立在我们最近的工作，解剖Treg 转录特征，确定了Treg细胞的胸腺分化和外周稳态 在独立的遗传控制下，并表明Treg细胞的淋巴外定位是 由TCR亚组和亚表型调节。我们拟研究：1）细胞机制， 调节性T细胞及其伴侣的稳态控制。我们将继续评估Treg群体 动力学，也扩展了我们对淋巴细胞外群体的结果，特别是Treg细胞， 渗透受伤的肌肉并帮助控制其再生。我们还将分析 自身免疫性病变中Treg和NK细胞之间的相互作用2）向Treg表型的继发性转化： 重要性和特异性。成熟的CD 4 * 淋巴细胞向FoxP 3+状态的新转化可以是 通过慢性抗原刺激，淋巴细胞减少驱动的体内稳态扩增，或IL 2 +GFP， 体外次级Treg分化对于自身或肠道植物群的耐受性可能是重要的，并且现在已经被很好地证实。 确立了习我们正试图找出这些细胞的特异性（在多克隆环境中，非- 在TCR库和转录特征方面，以及作为在TCR基因组中的变异的函数， 肠道微生物组3)Treg细胞稳态的分子决定论。我们将建立在我们的描述 Treg基因开关，其中Treg转录标签可以稳定地开启，以自我调节的方式， 增强模式，通过表达FoxP 3和任何几种辅因子。我们将更详细地分析 此交换机的requirem^int。我们将在此背景下探讨FoxPS与其他TF的相互作用， 特别是在RNAi筛选中，其将探测在该开关行为中对特定辅因子的需求。 相关性（参见说明）： 这些实验将探索导致变异的细胞机制和调控途径 FoxP 3 + T调节细胞的分化和稳态。结果应该会导致一个更好的 了解这一人群是免疫调节的关键，并影响几种自身免疫和 炎症性疾病。

Peripheral mechanisms of tolerance and immunoregulation are essential to prevent the damage potentially caused by autoreactive T cells that escape thymic tolerance induction. Among these, Treg cells expressing the FoxP3 transcription factor are the best characterized, with their ability to suppress immune and autoimmune responses, and their exciting potential for human therapy. They represent a constant proportion of CD4+ cells in lymphoid organs of a given individual, but vary markedly between individuals in a species. Beyond known roles for IL2 and TGFp, the mechanisms and genetic variation that control the selection and homeostatic balance of the Treg pool remain unclear. Following studies on the survival and homeostasis of "conventional" T cells in the previous cycle, we propose to build on our recent work that dissected the Treg transcriptional signature, established that the thymic differentiation and peripheral homeostasis of Treg cells are under independent genetic control, and showed that the extra-lymphoid localization of Treg cells are conditioned by TCR sub-repertoires and sub-phenotypes. We propose to study: 1) Cellular mechanisms of homeostatic control of Treg cells and their partners. We will continue to assess Treg population dynamics, also extending our results on extra-lymphoid populations, and in particular Treg cells which infiltrate the injured muscle and aid controlling its regeneration. We will also analyze the mechanisms of the interplay between Treg and NK cells in autoimmune lesions 2) Secondary conversion to Treg phenotype: significance and specificity. Neo-conversion of mature CD4* lymphocytes to a FoxP3+ state can be achieved by chronic antigen stimulation, lymphopenia-driven homeostatic expansion in vivo, or IL2+GFP in vitro. Secondary Treg differentiation may be important for tolerance to self or to gut flora, and is now well established. We are attempting to work out the specificity of these cells (in polyclonal settings, non- transgenic), in terms of TCR repertoire and of transcriptional signature, and as a function of variation in the gut microbiome. 3) Molecular determinism of Treg cell homeostasis. We will build upon our description of the Treg genetic switch, in which the Treg transcriptional signature can be stably switched on, in a self- reinforcing mode, by expression of FoxP3 and any of several co-factors. We will analyze in more detail the requirem^ints for this switch. We will explore the interactions of FoxPS with other TFs in this context, in particular in an RNAi screen which will probe the requirement for specific cofactors in this switch behavior. RELEVANCE (See instructions): These experiments will explore the cellular mechanisms and regulatory pathways that lead to variations in the differentiation and homeostasis of FoxP3+ T regulatory cells. The results should lead to a better understanding of this population that is key to immune regulation, and impacts several autoimmune and inflammatory diseases.