The Colitogenic Capacity of Gut Homing Recent Thymic Emigrants

描述（由申请人提供）：最年轻的外周T细胞被称为近期胸腺移行细胞或RTEs，淋巴细胞构成新生儿的整个T细胞池，在成人中对于维持T细胞多样性和在淋巴清除性病毒感染或治疗后重建幼稚T细胞池至关重要。使用小鼠模型系统，其中RTEs可以从大量的外周T细胞中区分出来，我们已经表明，刺激的RTEs表现出减少的增殖，减少细胞因子的产生，并改变表面表型相比，类似的处理成熟的T细胞。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。我们怀疑T细胞发育的这2-3周过渡期允许年轻T细胞扫描淋巴外周以寻找在胸腺中不表达的自身抗原，并对它们产生耐受性。初步数据表明，RTEs表达高水平的肠道归巢受体，并可能在离开胸腺后首先运输到肠道。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被保留在那里，从而降低RTE的大肠杆菌感染潜力。提出的实验包括以下具体目标：具体目标1：确定RTE是否优先归巢肠道。这些实验将比较功能性肠道归巢受体在RTEs和成熟幼稚外周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。 具体目标2：评估RTE肠道归巢是否依赖于肠道抗原。这些实验将确定在抗生素处理的小鼠中或在肠上皮细胞或肠道细菌中表达T细胞特异性识别的抗原的小鼠中，RTE在肠相关淋巴组织中的定位和保留是否受到干扰。 具体目标3：研究肠道归巢RTE是否对肠道抗原耐受。这些实验将比较RTE和成熟T细胞的致大肠杆菌的潜力，并确定RTE肠道归巢的阻断或肠道微生物群的消除是否与更大的RTE致大肠杆菌的潜力相关。进一步的实验将比较当在肠上皮细胞或管腔中遇到特异性抗原时，RTE和成熟T细胞诱导结肠炎的能力。 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。最近在小鼠和人类的胸腺移民抑制免疫功能，我们假设的属性使他们敏感的耐受性诱导。我们将在结肠炎的小鼠模型中测试这一假设，结肠炎是一种慢性炎症性疾病，部分由T细胞识别肠道抗原引发。了解驱动结肠炎的免疫失调的最终目标是增加可用于治疗这种疾病的药物谱。

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.