CHARACTERIZATION OF RECENT THYMIC EMIGRANTS

描述（由申请人提供）：健康人的外周T细胞池由胸腺输出和外周稳态维持。胸腺在个体的一生中输出新生成的T细胞。这些细胞被称为近期胸腺移植物或rte，主要存在于新生儿期和成人中，对于维持T细胞多样性和通过感染或治疗干预在淋巴细胞枯竭后重建初始T细胞库至关重要。通过小鼠模型系统，可以将rte与大部分外周T细胞区分开来，现在可以清楚地看到，T细胞在胸腺流出后的2-3周内继续成熟。与类似处理的成熟T细胞相比，活化的CD4和CD8 rte表现出增殖减弱、细胞因子产生减少和表面抗原表型改变。这种独特的功能特征在rte进入成熟的外周T细胞池后仍能持续存在。拟议的实验包括以下具体目的：具体目的1：确定CD4 rte是否在体内表现出对Th1和th2谱系的偏见。这些实验将确定rte体内是否存在Th1反应缺陷和Th2反应增强。特异性目的2：研究rte细胞因子位点的表观遗传控制是否与成熟的初始T细胞不同。这些实验将评估谱系承诺的CD4 rte的可塑性，并将研究初始和极化CD4 rte的Th2、Il2和Ifng位点以及初始和活化CD8 rte的Il2和Ifng位点的染色质修饰，以了解区分rte与成熟T细胞的细胞因子表达遗传变化背后的机制。特异性目的3：分析rte和成熟幼稚T细胞中TCR信号转导的比较强度。这些实验将研究TCR下游导致RTE反应抑制的事件，调节能量诱导和记忆/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功能特征与能量之间的关系，并探讨RTE解释环境线索的方式与成熟的同行不同。这些研究的总体目标是了解rte的生物学，rte是外周T细胞的一个关键但研究不足的群体。

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.