The Colitogenic Capacity of Gut Homing Recent Thymic Emigrants

描述（由申请人提供）：最年轻的外周T细胞被称为最近胸腺移植物或rte，这些淋巴细胞构成了新生儿的整个T细胞库，对于维持T细胞多样性和在淋巴消融病毒感染或治疗后重建原始T细胞库至关重要。通过小鼠模型系统，rte可以与大部分外周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rte表现出增殖减弱、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细胞池后仍能持续存在。我们怀疑，这2-3周的T细胞发育过渡期允许年轻的T细胞扫描淋巴样周围，寻找胸腺中未表达的自身抗原，并对它们产生耐受性。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保留在那里，从而降低了RTE的结肠炎潜力。拟议的实验包括以下具体目的：具体目的1：确定rte是否优先返回肠道。这些实验将比较功能性肠归巢受体在rte和成熟na - ve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。特异性目的2：评估RTE肠道归巢是否依赖于肠道抗原。这些实验将确定在抗生素治疗的小鼠或在肠道上皮细胞或共生菌中表达T细胞特异性识别的抗原的小鼠中，RTE在肠道相关淋巴组织中的定位和保留是否受到干扰。特异性目的3：研究肠道归巢rte是否对肠道抗原产生耐受。这些实验将比较RTE和成熟T细胞的结肠炎潜能，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结肠炎潜能相关。进一步的实验将比较rte和成熟T细胞在肠道上皮细胞或管腔中遇到特异性抗原时诱导结肠炎的能力。

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.