Antigen biased positive selection of CD4+ T cells

描述(由申请人提供)：积极选择胸腺中T细胞的多肽的性质仍然不明确。为了研究多肽在体内正选择中的作用，我们产生了表达类II限制性TCR的跨基因小鼠，该TCR专用于由抗体分子呈现的鸽子细胞色素C肽PCC(43-58)的类似物。将TCR转基因小鼠回交到同时缺失H2-M、恒定链和TCRA链的小鼠，由于缺乏内源选择肽(S)，跨性生成的胸腺细胞的发育受阻于CD_4+CD_8+期。然而，注射可溶性激动肽可以恢复这些胸腺细胞的阳性选择，使该模型成为第一个体内多肽诱导T细胞阳性选择的系统。因此，这项建议的具体目的如下：1：利用该体内系统，确定可启动CD4+T细胞阳性选择的可溶多肽的生物学特性。2：鉴定对CD4+T细胞有阳性选择作用的中性多肽。3.分析在不同体内环境中阳性选择的表达一种特定abTCR的CD4+T细胞的激活和生存需求。4：比较阳性选择开始后不久胸腺细胞的基因和蛋白质表达谱。

DESCRIPTION (provided by the applicant): The nature of peptides that positively select T cells in the thymus remains poorly defined. To examine the role of peptides during positive selection in vivo, we generated transpenic mice expressing class II restricted TCR specific for analogs of a pigeon cytochrome C peptide PCC(43-58) presented by the Ab molecule. The TCR transgenic mice were backcrossed to mice simultaneously lacking H2-M, invariant chain and TCRa-chain, where development of transpenic thymocytes is arrested at the CD4+CD8+ stage, due to the lack of the endogenously selecting peptide(s). However, injection of the soluble agonist peptide could restore positive selection of these thymocytes, making this model the first in vivo system of peptide induced positive selection of T cells. Hence, the specific aims of this proposal are as follow: 1: To determine biological properties of soluble peptides that can initiate positive selection of CD4+ T cells using this in vivo system. 2: To identify neutral peptides that positively select CD4+ T cells. 3: To analyze the activation and survival requirements of CD4+ T cells expressing one particular abTCR, positively selected in different in vivo environments. 4: To compare gene and protein expression profiles in thymocytes shortly following the onset of positive selection.