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Explore the cause of CDR3 shortening during thymocyte selection

探讨胸腺细胞选择过程中CDR3缩短的原因

基本信息

批准号：
18590178
负责人：
OGATA Masaki
金额：
$ 2.49万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590178/
关键词：
T cell receptor Thymic selection Thymic development MHC Antigen specificity Antigen recognition Tリンパ球選択分化胸腺

项目摘要

T cell receptor (TCR) is composed of alpha and beta chain subunits. TCR can specifically recognize an antigen-peptide presented on antigen presenting Dells with complementarily determining region 3 (CDR3) generated after gene rearrangement. We have previously reported that the length of CDR3 shortened along with thymic T cell development. However, it remains unknown why the alteration of CDR3 length occur during T cell development. To clarify the mechanism of CDR3 shortening, we planned to analyze an alteration of CDR3 length in TCR beta chain in detail and also examine whether the change is observed in TCR alpha chain.By using a set of congenic mice bearing different MHC haplotypes we disclosed that 1) CDR3 length in TCR beta shortened between CD4+CD8+ and either CD4+CD8- or CD4-CD8+ cells in thymus, that 2) CDR3 shortening was influenced by MHC haplotype, 3) the extent of CDR3 shortening varied considerably among Vbeta families and 4) there are similarities in the extent of CDR3 shor … More tening between homologous Vbeta subfamilies. We established an analysis method of CDR3 length in TCR alpha chain and performed the CDR3 length analysis with a large panel of primers specific for 29 Valpha families. We demonstrated in this study, for the first time, that CDR3 length shortened in both beta chain and alpha chain. In addition, we found that the extent of CDR3 shortening was heavily dependent not only on V beta chain but also Valpha chain.It is well-known that amino acid residues on MHC alpha-helix can interact with those located at TCR V regions through crystallographic studies of TCR/peptide-MHC molecules, which are crucial to antigen recognition. We speculated that only TCR that can ensure proper configuration between MHC and V regions should be selected thorough positive and negative selections, leading to alteration of CDR3 length. We revealed an interesting fact that topology of the TCR-peptide/MHC interaction has an impact on inherent diversity of TCR in terms of CDR3 length. Less

T细胞受体（TCR）由α和β链亚基组成。TCR可以特异性识别抗原呈递Dell上呈递的抗原肽，其具有基因重排后产生的互补决定区3（CDR 3）。我们以前曾报道过，随着胸腺T细胞的发育，CDR 3的长度沿着缩短。然而，在T细胞发育过程中，CDR 3长度的改变为什么会发生仍然是未知的。为了阐明CDR 3缩短的机制，我们计划详细分析TCR β链中CDR 3长度的变化，并检查TCR α链中是否观察到这种变化，通过使用一组携带不同MHC单倍型的同源小鼠，我们发现：1）胸腺中CD 4 + CD 8+细胞与CD 4 + CD 8-或CD 4-CD 8+细胞之间TCR β中CDR 3长度缩短，CDR 3缩短受MHC单倍型的影响，CDR 3缩短的程度在V β家族中差异很大， ...更多信息同源V β亚家族之间的连接。我们建立了TCR α链CDR 3长度的分析方法，并使用29个Valpha家族特异性的大组引物进行了CDR 3长度分析。我们在这项研究中首次证明，CDR 3的长度在β链和α链中都缩短了。另外，我们发现CDR 3的缩短程度不仅依赖于V β链，也依赖于Valpha链，通过对TCR/肽-MHC分子的晶体学研究，我们知道MHC α螺旋上的氨基酸残基可以与TCR V区的氨基酸残基相互作用，这对抗原识别至关重要。我们推测，只有能够确保MHC和V区之间正确配置的TCR才应该通过正向和负向选择来选择，从而导致CDR 3长度的改变。我们揭示了一个有趣的事实，即TCR-肽/MHC相互作用的拓扑结构对TCR在CDR 3长度方面的固有多样性有影响。少