CHARACTERIZATION OF RECENT THYMIC EMIGRANTS

描述（由申请人提供）：健康个体的外周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产生的T细胞。这些细胞，称为最近胸腺移民或RTEs，在新生儿期和成人中占主导地位，对于维持T细胞多样性和在通过感染或治疗干预进行淋巴细胞耗竭后重建幼稚T细胞库至关重要。使用小鼠模型系统，其中RTE可以与大量的外周T细胞区分开，现在清楚的是，T细胞在胸腺排出后持续成熟2-3周。与类似处理的成熟T细胞相比，活化的CD 4和CD 8 RTE表现出增殖减少、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细胞库后持续良好。具体目标1：确定体内CD 4 RTEs是否表现出对Th 1和Th 2谱系的偏倚。这些实验将确定RTEs是否在体内产生缺陷的Th 1应答和增强的Th 2应答。 具体目标2：研究RTE中细胞因子基因座的表观遗传控制是否与成熟幼稚T细胞中的表观遗传控制不同。这些实验将评估谱系定型的CD 4 RTE的可塑性，并将研究幼稚和极化的CD 4 RTE的Th 2、Il 2和Ifng基因座处以及幼稚和活化的CD 8 RTE的Il 2和Ifng基因座处的染色质修饰，以努力理解区分RTE与成熟T细胞的细胞因子表达的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信号转导的比较强度。这些实验将研究导致RTE应答减弱的TCR下游事件、调节无反应性诱导和记忆/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功能性状和无反应性之间的关系，并探讨RTE解释环境线索的方式，这是不同于他们的成熟同行。 这些研究的总体目标是了解RTEs的生物学，RTEs是一个关键但研究不足的外周T细胞群体。 公共卫生相关性：新产生的T细胞（或最近的胸腺移民）的稳定输出是维持整个生命的T细胞区室的多样性所必需的。最近的胸腺移民构成了新生儿外周T细胞池的大部分，并需要重建耗尽的幼稚T细胞池在成人。因此，了解最近的胸腺移民的生物学是至关重要的，以预测免疫反应的新生儿和成人淋巴细胞清除病毒感染或治疗干预。

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.