Regulatory T Cell Selection and Specificity

CD4+CD25+调节性T（Treg）细胞表达叉头转录因子Foxp3，并且对于维持对"扩展自我“的显性免疫耐受性是必需的，所述”扩展自我“包括自身蛋白和肠道微生物植物群。由于Foxp3突变导致的T reg细胞的全面衰竭导致全身性自身免疫、淋巴细胞增殖和过敏性调节异常的致死综合征，强调了T reg细胞对控制免疫应答的重要贡献。有两种类型的Treg细胞，即所谓的“天然”T reg（nT reg）细胞，其作为胸腺中的特定谱系出现，以及“诱导”T reg（iTreg）细胞，其由外周中的常规T细胞产生。该项目的广泛，长期目标是阐明Treg细胞成熟和功能的基本机制。本提案的具体目的是确定iT reg和nTreg细胞对耐受性的个体贡献，并剖析负责两种细胞类型之间功能差异的机制。拟定的研究将检验完全耐受需要iTreg和nT reg细胞的假设。我们假设，每种细胞类型提供了一个非冗余和协同作用，由不同的TCR库，基因表达模式的变化，和不同的功能属性授权。在拟定的实验中，我们将使用胸腺器官培养物来确定控制胸腺中nT reg选择的TCR亲和力要求。我们将采用精辟的遗传工具来功能性地定义iTreg和nT reg细胞群，这些细胞群用于通过过继转移免疫疗法拯救Foxp3缺陷小鼠和患有炎症性肠病的小鼠。这些研究将为Treg细胞维持显性耐受性的机制以及Treg细胞缺陷引起的免疫反应失调和自身免疫提供基础和临床前见解。

CD4+CD25+ regulatory T (Treg) cells express the forkhead transcription factor Foxp3 and are essential for the maintenance of dominant immunological tolerance to the 'extended self, which includes self proteins and the commensal microbial flora. Global failure of T reg cells due to mutations in Foxp3 results in a lethal syndrome of systemic autoimmunity, Iymphoproliferation, and allergic dysregulation, underscoring the essential contribution of T reg cells to the control of immune responses. There are two types of Treg cells, the so called 'natural' T reg (nT reg) cells that arise as a specific lineage in the thymus, and 'induced' T reg (iTreg) cells that are generated from conventional T cells in the periphery. The broad, longterm objective of this project is to elucidate the fundamental mechanisms underpinning Treg cell maturation and function. The specific aims of this proposal are intended to identify the individual contributions of iT reg and nTreg cells to tolerance and to dissect the mechanisms responsible for functional distinctions between the two cell types. The proposed studies will test the hypothesis that complete tolerance requires both iTreg and nT reg cells. We postulate that each cell type serves a non-redundant and synergistic role, mandated by distinct TCR repertoires, variations in gene expression patterns, and divergent functional attributes. In the proposed experiments, we will use thymic organ cultures to establish the TCR affinity requirements that control nT reg selection in the thymus. We will employ incisive genetic tools to functionally define the iTreg and nT reg cell populations used to rescue Foxp3 deficient mice and mice with inflammatory bowel disease by adoptive transfer immunotherapy. These investigations will provide fundamental and preclinical insights into mechanisms governing the maintenance of dominant tolerance by Treg cells, as well as the dysregulated immune responses and autoimmunity unleashed by Treg cell deficiency.