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

当特定的适应性免疫反应针对自身抗原时，就会产生自身免疫性疾病，而免疫系统在健康状况下应该能够耐受这种免疫系统，其中一种破坏耐受性的机制可以通过分子拟态模型来解释，其中自我抗原。反应性T细胞是由携带与自身抗原肽密切相关的T细胞表位的传染性微生物引发的。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预期。在本研究中，我们分析了经过轻微修饰的抗原肽（改变的肽配体；APL）刺激的 T 细胞的信号转导途径，表征了相关的自身反应性 T 细胞克隆识别的 T 细胞表位的多样性。患有自身免疫性疾病，并鉴定出可被 T 细胞克隆识别的微生物来源的非自身抗原肽，我们获得了以下结果：1）一些部分激动性。当源自非自体链球菌肽的 APL 在抗原呈递细胞表面过度表达时，它们可以刺激同源人 CD4^+ T 细胞（Th 细胞）克隆增殖。独特之处在于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，所有这些显然都是在用原始抗原肽刺激的T细胞中观察到。2)我们使用CLIP取代的不变链建立了T细胞表位表达库，并使用修饰的库鉴定了Th细胞克隆识别的多种T细胞表位。其中随机氨基酸残基被缩小为三个连续的残基，我们表征了来自 IDDM 患者的 GAD65 反应性 Th 细胞克隆的表位简并性，并鉴定了Th 细胞克隆交叉反应的肺炎链球菌和金黄色葡萄球菌衍生表位较少。

项目成果

期刊论文数量（250）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Yamada,K.: "Identification of a novel autoantigen UACA in patients with panuveitis."Biochem.Biophys.Res.Comm.. (in press).

Yamada,K.：“全葡萄膜炎患者中新型自身抗原 UACA 的鉴定。”Biochem.Biophys.Res.Comm..（出版中）。

DOI：
发表时间：
期刊：
影响因子：
0
作者：
通讯作者：

尹忠秀: "Annual Review免疫2000"中外医学社. 9(280-288) (1999)

Tadahide Yoon：“免疫学年度评论 2000”，Chugai Igakusha 9(280-288) (1999)。

DOI：
发表时间：
期刊：
影响因子：
0
作者：
通讯作者：

Zhang XP: "Puzon-McLaughlin W, Irie A, Kovach N, Prokopishyn NL, Laferte S, Takeuchi K, Tsuji T, Takada Y. α3β1 adhesion to laminin-5 and invasin : critical and differential role of integrin residues clustered at the boundary between α3 N-terminal repeats

张 XP：“Puzon-McLaughlin W、Irie A、Kovach N、Prokopishyn NL、Laferte S、Takeuchi K、Tsuji T、Takada Y。α3β1 对层粘连蛋白 5 和侵入蛋白的粘附：聚集在边界的整联蛋白残基的关键和差异作用α3 N 末端重复序列之间