ANTIGEN BIASED POSITIVE SELECTION NEONATAL CD4+ T CELLS

描述(改编自申请者的描述)：新的T细胞 在胸腺中广泛产生，主要从胎儿到幼年。 与自身MHC/肽微妙相互作用的未成熟T细胞(胸腺细胞) 胸腺上皮细胞正向选择复合体。此外， 表达T细胞受体(TCR)的胸腺细胞相互作用太强 胸腺树突状细胞对自身MHC/肽复合体的负性选择 细胞和巨噬细胞。自源性多肽在血管紧张素转化过程中的作用 T细胞的选择是无可争辩的。然而，机制是如何 不同自身MHC/肽复合体选择未成熟T细胞残留物 不清楚。 这项建议使用了最近开发的使用单一 与II类MHC共价结合的多肽研究CD_4~+T细胞谱系 体内细胞选择。这项提案的主要目标是测试 假设新生儿外周血中的CD4+T细胞 由新肽诱导的胸腺选择控制。因此，具体来说， 目标一调查人员将确定接触残留物之间的 MHC/肽复合体和TCR影响所选T的谱系 细胞。接下来，调查人员将测试自我多样性的作用 衍生多肽对选定新生儿的CD4+T细胞光谱的影响。这个 第三个特定目的将检测转基因TCR的阳性选择 通过体内给药合成多肽诱导新生儿 选择此TCR。最后，最后一个具体目标将评估是否 体内给药的大侧链多肽可以选择限制性的 一组具有预测的抗原特异性的新的CD4+T细胞。

DESCRIPTION (Adapted from Applicant's Description): New T cells are extensively generated in the thymus, mainly from fetal to young age. Immature T cells (thymocytes) that subtly interact with self MHC/peptide complexes are positively selected by thymic epithelial cells. Furthermore, thymocytes that express T cell receptors (TCRs) that interact too strongly with self MHC/peptide complexes are negatively selected by thymic dendritic cells and macrophages. The role of self derived peptides in the process of selection of T cells is indisputable. However, the mechanism of how different self MHC/peptide complexes select immature T cells remains unclear. This proposal uses the recently developed strategy of the use of single peptides covalently bound to class II MHC to study the repertoire of CD4+ T cells selection in vivo. The major goal of this proposal is to test the hypothesis that in neonates the peripheral repertoire of CD4+ T cells can be controlled by neopeptide-inducible thymic selection. Therefore, in specific aim one the investigators will determine how the contact residues between the MHC/peptide complex and TCR influence the repertoire of the selected T cells. Next, the investigators will test the role of the diversity of self derived peptides on the spectrum of selected neonates in CD4+ T cells. The third specific aim will test positive selection of the transgenic TCR induced in neonates by an in vivo administration of synthetic peptide that selects this TCR. Finally, the last specific aim will evaluate whether peptides with large side chains administered in vivo can select a restricted set of new CD4+ T cells with predicted antigen specificity.