Characterization of Recent Thymic Emigrants

描述（由申请人提供）：近期胸腺移行细胞（RTEs）是淋巴外周中最年轻的T细胞，对于接种新生儿淋巴外周和重建新生儿淋巴细胞至关重要。在接受脐带血或从淋巴清除性病毒感染或治疗中恢复的成人中检测T细胞池。通过在RAG 2 p-GFP转基因小鼠中将RTE鉴定为GFP+外周T细胞，我们和其他人已经表明RTE在外周中停留的前3周经历表型和功能成熟。在这个过渡 在此期间，小鼠和人中的RTE在用抗原刺激后表现出增殖减少和细胞因子分泌改变。拟议实验的目标是了解免疫功能受抑制的进化保守和发育调节期的基础。我们将测试的假设，强有力的初步数据的基础上，即RTEs响应低亲和力配体获得的能力，侵入组织（从而获得暴露于自身抗原）和耐受诱导的敏感性提高。我们将使用糖尿病诱导和同种异体妊娠来了解胸腺后成熟的益处，并使用肿瘤根除来了解其风险。在该竞争性更新中提出的实验包括以下具体目的：具体目的1：比较RTE和成熟T细胞遇到外周自身抗原的应答。这些实验将检验以下假设：与成熟T细胞相比，在糖尿病模型系统中，RTE是侵入性的，但在识别自身抗原时易于耐受。 具体目标2：比较RTEs和成熟T细胞遇到不同亲和力的肿瘤抗原的反应。这些实验将检验以下假设：与成熟T细胞相比，在肿瘤模型系统中，RTE是侵入性的，但在识别低亲和力配体时易于耐受。 具体目标3：探讨调节性T细胞（Treg）诱导和Treg敏感性的RTEs。这些实验将确定增强的Treg诱导和/或对Treg介导的抑制的敏感性是否影响RTE功能。加强我们对胸腺后成熟的理解将有助于我们预测在T细胞发育的这个阶段增强免疫功能的下游影响，无论是正面的还是负面的，这是改善新生儿疫苗接种策略的一个有价值的目标，增强放射或化疗后的抗肿瘤反应，促进HIV感染者T细胞功能的逆转录病毒治疗后恢复。

DESCRIPTION (provided by applicant): Recent thymic emigrants (RTEs) are the youngest T cells in the lymphoid periphery, and are crucial for seeding the neonatal lymphoid periphery and for reconstituting the na?ve T cell pool in adults receiving umbilical cord blood or recovering fro lymphoablative viral infection or therapy. By identifying RTEs as GFP+ peripheral T cells in RAG2p-GFP transgenic mice, we and others have shown that RTEs undergo phenotypic and functional maturation for the first 3 weeks of residence in the periphery. During this transitional period, RTEs in both mice and humans exhibit diminished proliferation and altered cytokine secretion upon stimulation with antigen. The goal of the proposed experiments is to understand the basis for this evolutionarily conserved and developmentally regulated period of depressed immune function. We will test the hypothesis, based on strong preliminary data, that RTEs respond to low affinity ligands by acquiring both the capacity to invade tissues (thereby gaining exposure to self-antigens) and a heightened sensitivity to tolerance induction. We will use diabetes induction and allogeneic pregnancy to understand the benefits of post-thymic maturation, and tumor eradication to understand its risks. Experiments proposed in this competitive renewal are encompassed by the following specific aims: Specific Aim 1: To compare the response of RTEs and mature T cells encountering peripheral self- antigen. These experiments will test the hypothesis that, compared to mature T cells, RTEs are invasive yet prone to tolerance upon recognition of self-antigens in a diabetes model system. Specific Aim 2: To compare the response of RTEs and mature T cells encountering tumor antigens of varying affinity. These experiments will test the hypothesis that, compared to mature T cells, RTEs are invasive yet prone to tolerance upon recognition of low affinity ligands in a tumor model system. Specific Aim 3: To explore regulatory T cell (Treg) induction and Treg sensitivity of RTEs. These experiments will determine whether enhanced induction of Tregs and/or sensitivity to Treg-mediated suppression impact RTE function. Enhancing our understanding of post-thymic maturation will help us anticipate the downstream impact, both positive and negative, of boosting immune function at this stage of T cell development, a worthy goal for improving vaccination strategies in neonates, enhancing anti-tumor responses following radio- or chemotherapy, and promoting post-retroviral therapy recovery of T cell function in HIV infected individuals.