CHARACTERIZATION OF RECENT THYMIC EMIGRANTS

描述(申请人提供)：健康人的外周T细胞库由胸腺输出和外周动态平衡维持。胸腺在人的一生中输出新生成的T细胞。这些细胞被称为新近的胸腺移行者或RTES，在新生期和成人中占主导地位，对于维持T细胞的多样性和通过感染或治疗干预而导致淋巴枯竭后重建原始T细胞池至关重要。在小鼠模型系统中，RTES可以与大部分外周T细胞区分开来，现在可以清楚地看到，T细胞在胸腺出口后继续成熟2-3周。与类似处理的成熟T细胞相比，活化的CD4和CD8RTE表现出增殖减少，细胞因子产生减少，表面抗原表型改变。这种独特的功能特征在RTE进入成熟的外周T细胞库后持续很长时间。拟议的实验包括以下具体目标：具体目标1：确定在体内CD4RTE是否显示出对Th1和Th2谱系的偏见。这些实验将确定RTES是否在体内安装缺陷的Th1反应和增强的Th2反应。特定目的2：研究RTES细胞因子基因座的表观遗传控制是否与成熟的幼稚T细胞不同。这些实验将评估谱系决定的CD4rte的可塑性，并将研究幼稚和极化的CD4rte的Th2、IL2和IFNG基因以及幼稚和激活的CD8rte的IL2和IFNG基因的染色质修饰，以努力了解区别于成熟T细胞的细胞因子表达可遗传变化背后的机制。具体目的3：分析RTE和成熟幼稚T细胞中TCR信号转导的相对强度。这些实验将研究TCR下游导致RTE反应受抑的事件，调节无能诱导和记忆/效应细胞命运决定的转录因子的表达，以及配体亲和力和抗原持久性对RTE功能的影响。这些实验的重点是了解RTE功能特征和无能之间的关系，并探索RTE解释环境线索的方式不同于他们的成熟同行。这些研究的总体目标是了解RTE的生物学，这是一种关键但未被充分研究的外周T细胞群体。 公共卫生相关性：需要稳定输出新产生的T细胞(或最近的胸腺移民)，以在一生中保持T细胞室的多样性。最近的胸腺移居者构成了新生儿外周T细胞库的大部分，并且需要在成人中重建耗尽的初始T细胞库。因此，了解新近移居的胸腺的生物学对于预测新生儿和从淋巴耗竭病毒感染或治疗干预中恢复的成年人的免疫反应至关重要。

DESCRIPTION (provided by applicant): The peripheral T cell pool in healthy individuals is maintained by both thymic output and peripheral homeostasis. The thymus exports newly generated T cells throughout the lifetime of the individual. These cells, called recent thymic emigrants or RTEs, predominate in the neonatal period and in the adult, are crucial for maintaining T cell diversity and in reconstituting the naive T cell pool following lymphodepletion through infection or therapeutic intervention. Using a mouse model system in which RTEs can be distinguished from the bulk of peripheral T cells, it is now clear that T cells continue to mature for 2-3 weeks after thymic egress. Activated CD4 and CD8 RTEs exhibit diminished proliferation, decreased cytokine production, and altered surface antigen phenotype compared to similarly treated mature T cells. This distinct functional profile lasts well after RTEs have entered the mature peripheral T cell pool. Proposed experiments encompass the following specific aims: Specific Aim 1: To determine whether CD4 RTEs show a bias against the Th1 and toward theTh2 lineage in vivo. These experiments will determine whether RTEs mount deficient Th1 responses and enhanced Th2 responses in vivo. Specific Aim 2: To investigate whether the epigenetic control of cytokine loci in RTEs is distinct from that in mature naive T cells. These experiments will assess the plasticity of lineage-committed CD4 RTEs and will investigate chromatin modifications at the Th2, Il2, and Ifng loci of naive and polarized CD4 RTEs and at the Il2 and Ifng loci of naive and activated CD8 RTEs, in an effort to understand the mechanism behind the heritable changes in cytokine expression that distinguish RTEs from mature T cells. Specific Aim 3: To analyze the comparative strength of TCR signal transduction in RTEs and mature naive T cells. These experiments will investigate the events downstream of the TCR leading to dampened RTE responses, the expression of transcription factors that regulate anergy induction and memory/effector cell fate decisions, and the impact of ligand affinity and antigen persistence on RTE function. The focus of these experiments is to understand the relationship between RTE functional traits and anergy and to probe the manner in which RTEs interpret environmental cues that is distinct from their mature counterparts. The overall goal of these studies is to understand the biology of RTEs, a key but under-studied population of peripheral T cells. PUBLIC HEALTH RELEVANCE: The steady export of newly generated T cells (or recent thymic emigrants) is required to maintain the diversity of the T cell compartment throughout life. Recent thymic emigrants make up the bulk of the peripheral T cell pool in neonates, and are required to reconstitute the depleted naive T cell pool in adults. Thus, understanding the biology of recent thymic emigrants is crucial to predicting immune responses in neonates and in adults recovering from lymphodepleting viral infections or therapeutic interventions.