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THE DIVESITY IN ANTIGEN RECOGNITION AND RESPONSE OF ANTIGEN-SPECIFIC HUMAN CD4^+ T-CELL CLONES

抗原特异性人类 CD4^ T 细胞克隆的抗原识别和反应的多样性

基本信息

批准号：
11557027
负责人：
NISHIMURA Yasuharu
金额：
$ 8.58万
依托单位：
KUMAMOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11557027/
关键词：
autoimmune diseases tolerance self-reactive T cell molecular mimicry altered peptide ligand CLIP-substituted invariant chain epitope expression library CD4^+T細胞 MHCクラスII分子インバリアント鎖 CLIP 発現クローニング HLAクラスII分子エピトープライブラリー

项目摘要

Autoimmune diseases are developed when a specific adaptive immune response is directed against self antigens, to which the immune system is supposed to be tolerated in healthy condition. One of the hypothesized mechanisms that break the tolerance is explained by a molecular mimicry model, where self-reactive T cells were primed by infectious microorganisms carrying T-cell epitopes closely-related to the self-antigenic peptides. Indeed, evidence is accumulating that the degeneracy in epitopes recognized by a T cell clone is higher than that expected before. In the present study, we analyzed the signal transduction pathways of the T cells stimulated with slightly modified antigenic peptides (altered peptide ligands ; APLs), characterized the diversity of the T-cell epitopes recognized by self-reactive T-cell clones associated with an autoimmune disease, and identified microorganism-derived non-self antigenic peptides that were recognized by the T-cell clones. We obtained the following re … More sults :1) Some partially agonistic APLs derived from a non-self streptococcal peptide could stimulate the cognate human CD4^+ T-cell (Th cell) clone to proliferate when they were over-expressed on the surface of antigen presenting cells. However, the proliferative T-cell responses were unique in that they were not accompanied with detectable T-cell receptor (TCR)-proximal signaling events such as phosphorylation of ZAP-70 and LAT and down-regulation of the TCR, all of which were apparently observed in the T cells stimulated with the original antigenic peptide.2) We established a T-cell epitope-expression library using CLIP-substituted invariant chain and identified diverse T-cell epitopes that were recognized by Th-cell clones. Using the modified libraries in which randomized amino acid residues were narrowed down into three successive ones, we characterized the degeneracy in the epitopes of the GAD65-reactive Th-cell clones derived from IDDM patients and identified the Streptcoccus pneumoniae- and Staphylococcus aureus-derived epitopes to which the Th-cell clones cross-reacted. Less

当特异性适应性免疫应答针对自身抗原时，发展自身免疫性疾病，免疫系统被认为在健康状况下是耐受的。打破耐受性的假设机制之一由分子模拟模型解释，其中自身反应性T细胞由携带与自身抗原肽密切相关的T细胞表位的感染性微生物引发。事实上，越来越多的证据表明，T细胞克隆识别的表位的简并性高于以前的预期。在本研究中，我们分析了信号转导途径的T细胞刺激略有修改的抗原肽（改变的肽配体; APLs），其特征在于的多样性的T细胞表位识别的自身反应性T细胞克隆与自身免疫性疾病，并确定微生物来源的非自身抗原肽，被识别的T细胞克隆。我们获得了以下结果： ...更多信息结果：1）非自身链球菌肽部分激动性APLs在抗原提呈细胞表面过表达时，可刺激同源的人CD 4 ^+ T细胞（Th细胞）克隆增殖。然而，增殖性T细胞应答是独特的，因为它们不伴随可检测的T细胞受体（TCR）近端信号传导事件，例如ZAP-70和LAT的磷酸化以及TCR的下调，所有这些都明显地在用原始抗原肽刺激的T细胞中观察到。2）我们使用CLIP建立了T细胞表位表达文库。取代不变链并鉴定了Th细胞克隆识别的多种T细胞表位。使用修改后的库，其中随机氨基酸残基被缩小到三个连续的，我们的特点是简并性的GAD 65反应性Th细胞克隆来自IDDM患者的表位，并确定了肺炎链球菌和金黄色葡萄球菌衍生的表位的Th细胞克隆交叉反应。少