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Molecular basis for T cell repertoire selection in the thymus

胸腺中 T 细胞库选择的分子基础

基本信息

批准号：
11694289
负责人：
FUKUI Yoshinori
金额：
$ 4.35万
依托单位：
KYUSHU 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-11694289/
关键词：
MHC T cell receptor antigenic peptides positive and negative selection autoimmunity 胸腺内T細胞分化正の選択 MHC TCR T細胞レパートリー単一MHC ペプチド複合体 CDR3

项目摘要

T cell repertoire is shaped through the recognition of MHC/self-peptide complex by TCRs in the thymus. However, diversity of self-peptide precluded analyzing this interaction at a molecular level. To overcome this problem, we have developed transgenic-knockout mice where MHC molecules are occupied with a single defined peptide. By analyzing these mice, we found that 1) the same MHC/peptide complex, being affected by its expression level in the thymus, can serve as a ligand for both positive and negative selection and 2) while specific TCR-peptide interaction is involved even in positive selection, the amino acid residue of the peptides at TCR-contact remarkably affects the diversity of the selected T cell repertoire. On the other hand, it is well known that particular MHC alleles are associated with the susceptibility to organ-specific autoimmune diseases. We found that a line of transgenic-knockout mice expressing a single MHC/peptide complex at a quite low level in the thymus spontaneously develops peripheral nervous-specific autoimmune diseases. Since MHC molecules are accupied with a single defined peptide in these mice, these results suggest that MHC molecules determine the susceptibility to autoimmune diseases through T cell repertoire selection in the thymus.

T 细胞库是通过胸腺中的 TCR 识别 MHC/自肽复合物而形成的。然而，自肽的多样性阻碍了在分子水平上分析这种相互作用。为了克服这个问题，我们开发了转基因敲除小鼠，其中 MHC 分子被单个确定的肽占据。通过分析这些小鼠，我们发现：1）相同的 MHC/肽复合物，受其在胸腺中表达水平的影响，可以作为正选择和负选择的配体；2）虽然特定的 TCR-肽相互作用甚至参与正选择，但 TCR 接触处肽的氨基酸残基显着影响所选 T 细胞库的多样性。另一方面，众所周知，特定的 MHC 等位基因与器官特异性自身免疫性疾病的易感性相关。我们发现，一系列在胸腺中以相当低水平表达单一MHC/肽复合物的转基因敲除小鼠会自发地患上周围神经特异性自身免疫性疾病。由于这些小鼠中的 MHC 分子具有单一定义的肽，因此这些结果表明 MHC 分子通过胸腺中的 T 细胞库选择来确定对自身免疫性疾病的易感性。