Unconventional topology of self peptide-major histocompatibility complex binding by a human autoimmune T cell receptor
Unconventional topology of self peptide-major histocompatibility complex binding by a human autoimmune T cell receptor
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DOI：
10.1038/ni1187
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发表时间：
2005-05-01
影响因子：
30.5
通讯作者：
Wucherpfennig, KW
中科院分区：
文献类型：
--
作者：
Hahn, M;Nicholson, MJ;Wucherpfennig, KW
自身免疫性疾病是由逃避删除的自身反应性淋巴细胞引起的。在这里，我们已经确定了一个T细胞受体（TCR）的三分子复合物的结构，从多发性硬化症患者，导致转基因小鼠的自身免疫。该结构显示TCR拓扑结构与抗微生物TCR的拓扑结构显著不同。而不是集中在肽-主要组织相容性复合物上，该TCR仅接触N-末端肽段，并与主要组织相容性复合物螺旋进行不对称相互作用。的相互作用占主导地位的高变互补决定区3环，表明非常规的拓扑结构是可能的，因为独特的互补决定区3序列在重排过程中创建。这种拓扑结构减少了与肽的相互作用表面，并改变了CD 4缔合的几何形状。我们提出，不寻常的TCR结合特性可以允许自身反应性T细胞逃避删除。
Autoimmune diseases are caused by self-reactive lymphocytes that have escaped deletion. Here we have determined the structure of the trimolecular complex for a T cell receptor (TCR) from a patient with multiple sclerosis that causes autoimmunity in transgenic mice. The structure showed a TCR topology notably different from that of antimicrobial TCRs. Rather than being centered on the peptide-major histocompatibility complex, this TCR contacted only the N-terminal peptide segment and made asymmetrical interactions with the major histocompatibility complex helices. The interaction was dominated by the hypervariable complementarity-determining region 3 loops, indicating that unconventional topologies are possible because of the unique complementarity-determining region 3 sequences created during rearrangement. This topology reduces the interaction surface with peptide and alters the geometry for CD4 association. We propose that unusual TCR-binding properties can permit autoreactive T cells to escape deletion.