The Colitogenic Capacity of Gut Homing Recent Thymic Emigrants

描述(申请人提供)：最年轻的外周T细胞被称为近期胸腺移民者或RTES，淋巴细胞构成了新生儿的整个T细胞池，对成人来说是维持T细胞多样性和在淋巴清除性病毒感染或治疗后重建原始T细胞池的关键。在小鼠模型系统中，RTES可以与大多数外周T细胞区分开来，我们已经证明，与类似处理的成熟T细胞相比，受刺激的RTES表现出增殖减少、细胞因子产生减少和表面表型改变。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。我们怀疑，这2-3周的T细胞发育过渡期允许年轻的T细胞扫描淋巴样外周，寻找胸腺中没有表达的自身抗原，并对其产生耐受性。初步数据表明，rte表达高水平的肠道归巢受体，并可能在离开胸腺后首先进入肠道。我们假设，RTE有效地进入肠道淋巴组织，并通过与肠道来源的抗原相互作用而保留在那里，它们对这些抗原变得耐受，从而降低了RTE的致病潜力。拟议的实验包括以下具体目标：具体目标1：确定RTE是否优先定位于肠道。这些实验将比较功能性肠道归巢受体在RTE和成熟的自然外周T细胞上的表达，以及这些细胞在肠道相关淋巴组织中的分布。具体目的2：评估RTE肠道归巢是否依赖于肠道抗原。这些实验将确定RTE在肠道相关淋巴组织中的定位和滞留在抗生素治疗的小鼠中是否受到干扰，或者在表达T细胞特异性识别的抗原的肠道上皮细胞或共生细菌中的小鼠中是否受到干扰。具体目标3：研究肠道归巢RTE是否对肠道抗原产生耐受性。这些实验将比较RTE和成熟T细胞的致病潜力，并确定阻断RTE肠道归巢或消除肠道微生物群是否与更大的RTE致病潜力有关。进一步的实验将比较rtes和成熟T细胞在遇到肠道上皮细胞或肠腔中的特定抗原时诱发结肠炎的能力。 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。最近在小鼠和人类体内的胸腺移民者都抑制了免疫功能，我们推测这一特性使他们对耐受诱导敏感。我们将在结肠炎的小鼠模型中检验这一假设，结肠炎是一种慢性炎症性疾病，部分原因是T细胞对肠道抗原的识别。了解导致结肠炎的免疫失调是增加治疗这种疾病的药物谱的最终目标。

DESCRIPTION (provided by applicant): The youngest peripheral T cells are called recent thymic emigrants or RTEs, lymphocytes that constitute the entire T cell pool in neonates and are crucial in adults for maintaining T cell diversity and reconstituting the na¿ve T cell pool following lymphoablative viral infection or therapy. Using a mouse model system in which RTEs can be distinguished from the bulk of peripheral T cells, we have shown that stimulated RTEs exhibit diminished proliferation, decreased cytokine production, and altered surface phenotype compared to similarly treated mature T cells. This distinct functional profile lasts well after RTEs have entered the mature peripheral T cell pool. We suspect that this 2-3 week transitional period of T cell development allows young T cells to scan the lymphoid periphery for self-antigens that are not expressed in the thymus and to become tolerized to them. Preliminary data indicate that RTEs express high levels of gut homing receptors and may first traffic to the gut after leaving the thymus. We hypothesize that RTEs efficiently enter the gut lymphoid tissue and are retained there by interaction with gut-derived antigens to which they become tolerized, thereby diminishing RTE colitogenic potential. Proposed experiments encompass the following specific aims: Specific Aim 1: To determine whether RTEs preferentially home to the gut. These experiments will compare the expression of functional gut homing receptors on RTEs and mature na¿ve peripheral T cells and the distribution of these cells in the gut-associated lymphoid tissue. Specific Aim 2: To assess whether RTE gut homing is dependent on gut antigens. These experiments will determine whether RTE localization to and retention in the gut-associated lymphoid tissue is disturbed in antibiotic treated mice or in mice expressing in gut epithelial cells or commensal bacteria an antigen specifically recognized by T cells. Specific Aim 3: To investigate whether gut homing RTEs become tolerized to gut antigens. These experiments will compare the colitogenic potential of RTEs and mature T cells and determine whether blockade of RTE gut homing or elimination of the gut microbiota are associated with greater RTE colitogenic potential. Further experiments will compare the ability of RTEs and mature T cells to induce colitis when encountering specific antigen in the gut epithelial cells or lumen. 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 in both mice and humans have dampened immune function, a property we hypothesize makes them sensitive to tolerance induction. We will test this hypothesis in a mouse model of colitis, a chronic inflammatory disease triggered in part by T cell recognition of gut antigens. Understanding the immune dysregulation that drives colitis has the ultimate objective of augmenting the spectrum of agents available to treat this disease.