Reinsmoen N L, Bach F H
Department of Laboratory Medicine/Pathology and Surgery, University of Minnesota, Minneapolis 55455.
Hum Immunol. 1990 Jan;27(1):51-72. doi: 10.1016/0198-8859(90)90095-7.
In an effort to investigate the structure-function relationship of HLA class II molecules vis-à-vis alloepitope expression, cloned T-cell reagents were used to define polymorphic epitopes associated with DR and DQ molecules. DNA sequences of genes encoding allelic or isotypic DR or DQ molecules that appear to express the same T-cell-defined epitopes were compared in an attempt to identify association of shared sequences with shared epitopes. When sequence sharing is associated with shared epitope expression, we suggest that it is the shared sequence that encodes the epitope in question. Based on the hypothetical three-dimensional structure of the class II molecule, an approximation is made as to which parts of the HLA class II molecule are involved in alloepitope expression. T-cell clones were generated from cells primed against HLA-DR2 haplotypes representing the cellularly defined subgroups Dw2 or Dw21 (previously designated MN2, FJ0, or Tb24). Those clones determined to be DR- or DQ-directed based on monoclonal antibody inhibition assays were tested by panel cell analysis utilizing DR2-positive and DR2-negative target cells. The data support the concept that amino acids 67, 70, 71, and 74 for DR molecules and amino acids 57, 70, and 71 for DQ molecules, which appear to comprise one face of the alpha helix, are of primary importance in T-cell recognition. In other cases, sharing of both the second hypervariable region (amino acids 25-33) and the third hypervariable region (amino acids 67-74) appears necessary to explain epitope sharing for DR molecules. We emphasize that the involvement of these two hypervariable regions may indicate that alloepitope expression involves the complex of class II molecule plus peptide, with the second HVR primarily involved in determining which peptides are bound and the third in T-cell receptor (TcR) recognition and/or peptide binding; we do not rule out that conformational changes of the second HVR can induce conformational changes in the third HVR. Finally, shared alloepitopes detected by some clones could not be explained based on shared primary sequences.
为了研究人类白细胞抗原（HLA）Ⅱ类分子的结构与功能关系以及同种异体抗原表位的表达情况，使用克隆的T细胞试剂来确定与DR和DQ分子相关的多态性表位。对编码等位基因或同型DR或DQ分子的基因DNA序列进行比较，这些分子似乎表达相同的T细胞定义表位，试图确定共享序列与共享表位之间的关联。当序列共享与共享表位表达相关时，我们认为是共享序列编码了相关表位。基于Ⅱ类分子的假设三维结构，对HLAⅡ类分子的哪些部分参与同种异体抗原表位表达进行了近似推断。从针对代表细胞定义亚组Dw2或Dw21（先前称为MN2、FJ0或Tb24）的HLA - DR2单倍型致敏的细胞中产生T细胞克隆。根据单克隆抗体抑制试验确定为针对DR或DQ的那些克隆，利用DR2阳性和DR2阴性靶细胞通过板层细胞分析进行检测。数据支持这样的概念，即DR分子的第67、70、71和74位氨基酸以及DQ分子的第57、70和71位氨基酸，似乎构成α螺旋的一个面，在T细胞识别中至关重要。在其他情况下，似乎需要同时共享第二个高变区（第25 - 33位氨基酸）和第三个高变区（第67 - 74位氨基酸）才能解释DR分子的表位共享。我们强调，这两个高变区的参与可能表明同种异体抗原表位表达涉及Ⅱ类分子加肽的复合物，第二个高变区主要参与确定结合哪些肽，第三个高变区参与T细胞受体（TcR）识别和/或肽结合；我们不排除第二个高变区的构象变化会诱导第三个高变区的构象变化。最后，一些克隆检测到的共享同种异体抗原表位无法基于共享的一级序列来解释。
