Regulatory T Cell Selection and Specificity

CD4 CD25调节性T(Treg)细胞表达叉头转录因子Foxp3，对于维持对包括自身蛋白和共生微生物区系在内的扩展自我的显性免疫耐受是必不可少的。由于Foxp3基因突变导致的T-reg细胞的全球衰竭导致了一种致命的综合征，包括全身自身免疫、淋巴细胞增殖和变态反应性失调，这突显了T-reg细胞在免疫反应控制中的重要作用。有两种类型的Treg细胞，一种是在胸腺中作为特定谱系出现的所谓的自然的T细胞(NT Reg)，另一种是由外周的传统T细胞产生的“诱导的”T reg(ITreg)细胞。该项目的长期目标是阐明支持Treg细胞成熟和功能的基本机制。这项建议的具体目的是要确定it reg和ntreg细胞对耐受的单独贡献，并剖析导致这两种细胞类型功能差异的机制。拟议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，每种细胞类型都发挥着非冗余和协同作用，这是由不同的TCR谱系、基因表达模式的差异和不同的功能属性决定的。在拟议的实验中，我们将使用胸腺器官培养来建立控制胸腺中NT reg选择的TCR亲和力要求。我们将使用尖端的基因工具从功能上定义用于通过过继转移免疫治疗拯救Foxp3缺陷小鼠和炎症性肠病小鼠的iTreg和NT reg细胞群。这些研究将为Treg细胞维持优势耐受性的机制以及Treg细胞缺陷所引发的失调免疫反应和自身免疫提供基础和临床前的见解。

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.