HLA-DP4, the most frequent HLA II molecule, defines a new supertype of peptide-binding specificity
HLA-DP4, the most frequent HLA II molecule, defines a new supertype of peptide-binding specificity
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DOI：
10.4049/jimmunol.169.12.6928
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发表时间：
2002-12-15
影响因子：
4.4
通讯作者：
Maillère, B
中科院分区：
文献类型：
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作者：
Castelli, FA;Buhot, C;Maillère, B
在HLA-DP特异性中，HLA-DP 4特异性涉及至少两种分子，HLA-DPA 1 *0103/DPBI*0401（DP 401）和HLA-DPA 1 *0103/DPB 1 *0402（DP 402），它们彼此仅相差三个残基。它们一起以20-60%的等位基因频率存在于世界范围内，并且是最丰富的人类HLA II等位基因。引人注目的是，这些分子的肽结合特异性从未被研究过。因此，在这项研究中，我们报告了这两种分子的肽结合基序。我们首先建立了一个特异性的免疫纯化的HLA-DP 4分子的结合试验。使用多组合成肽，我们成功地定义了锚残基的氨基酸偏好。通过这些测定，我们还能够从过敏原和病毒及肿瘤抗原中鉴定新的肽配体。DP 401和DP 402表现出非常相似的识别模式，与复合物的分子建模一致。口袋P1和P6容纳主要的锚残基，并且有趣的是仅分别包含两个多态性残基β 86和β 11。这两个位置几乎是二态的，因此产生有限数量的口袋组合。两者合计，我们的研究结果支持HLA-DP分子之间存在三个主要的结合超型，并应显着有助于识别通用表位用于基于肽的疫苗的癌症，以及过敏性或传染性疾病。
Among HLA-DP specificities, HLA-DP4 specificity involves at least two molecules, HLA-DPA1*0103/DPBI*0401 (DP401) and HLA-DPA1*0103/DPB1*0402 (DP402), which differ from each other by only three residues. Together, they are present worldwide at an allelic frequency of 20-60% and are the most abundant human HLA II alleles. Strikingly, the peptide-binding specificities of these molecules have never been investigated. Hence, in this study, we report the peptide-binding motifs of both molecules. We first set up a binding assay specific for the immunopurified HLA-DP4 molecules. Using multiple sets of synthetic peptides, we successfully defined the amino acid preferences of the anchor residues. With these assays, we were also able to identify new peptide ligands from allergens and viral and tumor Ags. DP401 and DP402 exhibit very similar patterns of recognition in agreement with molecular modeling of the complexes. Pockets P1 and P6 accommodate the main anchor residues and interestingly contain only two polymorphic residues, beta86 and beta11, respectively. Both positions are almost dimorphic and thus produce a limited number of pocket combinations. Taken together, our results support the existence of three main binding supertypes among HLA-DP molecules and should significantly contribute to the identification of universal epitopes to be used in peptide-based vaccines for cancer, as well as for allergic or infectious diseases.