Point mutations define positions in HLA-DR3 molecules that affect antigen presentation.
Point mutations define positions in HLA-DR3 molecules that affect antigen presentation.
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点突变定义了 HLA-DR3 分子中影响抗原呈递的位置。
DOI：
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发表时间：
1990
影响因子：
11.1
通讯作者：
D. Pious
中科院分区：
文献类型：
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作者：
E. Mellins;B. Arp;D. Singh;B. Carreno;L. Smith;A. Johnson;D. Pious
主要组织相容性复合物 (MHC) 编码的 II 类分子的等位基因差异影响免疫原性肽与 II 类分子的结合以及 T 细胞对 MHC 分子-肽复合物的识别。迄今为止，还没有将这些功能广泛映射到人类 II 类分子的精细结构。为了确定 HLA-DR3 分子上参与向 T 细胞呈递抗原的位点，我们使用 HLA-DR3 特异性单克隆抗体来免疫选择 B 类淋巴母细胞系的突变体。我们定位了 HLA-DR3 分子中单个氨基酸取代的位点，并将这些结构变化与 HLA-DR3 限制性抗原特异性 T 细胞、同种异体特异性 T 细胞和同种异体抗 DR3 单克隆抗体的识别模式相关联。我们分析了七个突变。位于 DR β 链结构域 1 的第 74 位的一个突变影响了所有测试的 T 细胞的识别，而位于 DR β 链第 9、45、73、151 和 204 位以及 DR α 链第 115 位的其他突变则改变了某些 T 细胞的识别，但不改变其他 T 细胞的识别。每一种替代都会产生独特的 T 细胞刺激模式。此外，每个 T 细胞克隆都识别不同的突变体子集。这些结果表明DR3分子的不同残基参与将抗原呈递给不同的DR3限制性T细胞。这些研究进一步表明，最有可能影响肽结合的取代改变了同种反应性 T 细胞克隆和一些同种特异性抗体对 DR3 分子的识别。
Allelic differences in major histocompatibility complex (MHC)-encoded class II molecules affect both the binding of immunogenic peptides to class II molecules and the recognition of MHC molecule-peptide complexes by T cells. As yet, there has been no extensive mapping of these functions to the fine structure of human class II molecules. To determine sites on the HLA-DR3 molecule involved in antigen presentation to T cells, we used monoclonal antibodies specific for HLA-DR3 to immunoselect mutants of a B-lymphoblastoid line. We located the sites of single amino acid substitutions in the HLA-DR3 molecule and correlated these structural changes with patterns of recognition by HLA-DR3-restricted, antigen-specific T cells, allospecific T cells, and allospecific anti-DR3 monoclonal antibodies. We analyzed seven mutations. One mutation, at position 74 in domain 1 of the DR beta chain, affected recognition by all T cells tested, whereas others, at positions 9, 45, 73, 151, and 204 of the DR beta chain and position 115 of the DR alpha chain, altered recognition by some T cells, but not others. Each of the substitutions resulted in a unique pattern of T-cell stimulation. In addition, each T-cell clone recognized a different subset of the mutants. These results indicate that different residues of the DR3 molecule are involved in presentation of antigen to different DR3-restricted T cells. These studies further show that substitutions which most likely affect peptide binding alter recognition of DR3 molecules by an alloreactive T-cell clone and some allospecific antibodies.