Conformational differences in major histocompatibility complex-peptide complexes can result in alloreactivity.
Conformational differences in major histocompatibility complex-peptide complexes can result in alloreactivity.
复制标题
主要组织相容性复合肽复合物的构象差异会导致同种异体。
DOI：
10.1084/jem.179.1.213
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发表时间：
1994-01-01
期刊：
影响因子：
--
通讯作者：
Sherman LA
中科院分区：
文献类型：
--
作者：
Chattopadhyay S;Theobald M;Biggs J;Sherman LA
影响肽结合的I类主要组织相容性复合体（MHC）分子内的突变可导致强烈的同种异体反应。据信，这部分反映了每个MHC分子结合不同的内源性肽组。我们已经研究了由KB特异性细胞毒性T淋巴细胞（CTL）克隆识别的同种异体肽的代表性，这些克隆表达Kb或Kbm 8突变体。这些I类分子在肽结合沟的基础上突变不同，导致大多数Kb特异性CTL缺乏对bm 8靶标的识别，并且具有强的相互同种异体反应性。由于这些差异涉及肽结合沟底部的口袋，推测这些口袋有助于肽结合的亲和力，并且有证据表明突变体和野生型分子的肽结合存在差异，因此认为同种异体反应性最有可能是由于这些分子中的每一种结合不同的肽组。令人惊讶的是，从各种应答者，包括bm 8，KB特异性克隆识别的allopeptide，经常发现与野生型和突变的I类分子。尽管对于某些同种异体肽，通常发现与bm 8相关的肽的量小于与Kb相关的量，但通过增加相关肽的量不能恢复反应性。因此，在该特定突变体和野生型组合中观察到的同种异体反应性的基础不是相关同种异体肽的存在或不存在，而是肽-MHC复合物适应的不同构象。这些结果使我们能够得出结论，强烈的同种异体反应性反应可以导致T细胞识别的刺激和响应MHC分子之间的构象差异。
Mutations within the class I major histocompatibility complex (MHC) molecule that affect a peptide binding can result in strong allogeneic responses. It is believed this reflects, in part, binding of a different set of endogenous peptides by each MHC molecule. We have examined the representation of allopeptides recognized by Kb-specific cytotoxic T lymphocytes (CTL) clones among targets that express either the Kb or the Kbm8 mutant. These class I molecules mutationally differ by several residues at the base of the peptide binding groove resulting in lack of recognition of bm8 targets by most Kb-specific CTL, and in strong mutual alloreactivity. Since these differences involve pockets in the base of the peptide binding groove that are presumed to contribute to the affinity of peptide binding, and there is evidence for differences in peptide binding by the mutant and wild type molecule, it was considered most likely that alloreactivity was due to binding of different sets of peptides by each of these molecules. Surprisingly, the allopeptides recognized by Kb-specific clones from a variety of responders, including bm8, are often found associated with both the wild type and mutant class I molecules. Although for some allopeptides the amount of peptide normally found associated with bm8 is less than that associated with Kb, reactivity could not be restored by increasing the amount of the relevant peptide. Thus, the basis for much of the alloreactivity observed in this particular mutant and wild type combination is not the presence or absence of the relevant allopeptide but rather the different conformation adapted by the peptide-MHC complex. These results allow us to conclude that strong alloreactive responses can result from T cell recognition of conformational differences between the stimulation and responder MHC molecules.