School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China.
NHC Key Laboratory of Medical Virology and Viral Diseases, Chinese Center for Disease Control and Prevention, National Institute for Viral Disease Control and Prevention, Beijing, China.
Front Immunol. 2019 Jul 23;10:1709. doi: 10.3389/fimmu.2019.01709. eCollection 2019.
Human leukocyte antigen (HLA) alleles have a high degree of polymorphism, which determines their peptide-binding motifs and subsequent T-cell receptor recognition. The simplest way to understand the cross-presentation of peptides by different alleles is to classify these alleles into supertypes. A1 and A3 HLA supertypes are widely distributed in humans. However, direct structural and functional evidence for peptide presentation features of key alleles (e.g., HLA-A30:01 and -A30:03) are lacking. Herein, the molecular basis of peptide presentation of HLA-A30:01 and -A30:03 was demonstrated by crystal structure determination and thermostability measurements of complexes with T-cell epitopes from influenza virus (NP44), human immunodeficiency virus (RT313), and (MTB). When binding to the HIV peptide, RT313, the PΩ-Lys anchoring modes of HLA-A30:01, and -A30:03 were similar to those of HLA-A11:01 in the A3 supertype. However, HLA-A30:03, but not -A30:01, also showed binding with the HLA01:01-favored peptide, NP44, but with a specific structural conformation. Thus, different from our previous understanding, HLA-A30:01 and -A30:03 have specific peptide-binding characteristics that may lead to their distinct supertype-featured binding peptide motifs. Moreover, we also found that residue 77 in the F pocket was one of the key residues for the divergent peptide presentation characteristics of HLA-A30:01 and -A30:03. Interchanging residue 77 between HLA-A30:01 and HLA-A30:03 switched their presented peptide profiles. Our results provide important recommendations for screening virus and tumor-specific peptides among the population with prevalent HLA supertypes for vaccine development and immune interventions.
人类白细胞抗原 (HLA) 等位基因具有高度多态性，这决定了它们的肽结合基序和随后的 T 细胞受体识别。理解不同等位基因的肽交叉呈递的最简单方法是将这些等位基因分类为超型。A1 和 A3 HLA 超型在人类中广泛分布。然而，缺乏关键等位基因（例如 HLA-A30:01 和 -A30:03）的肽呈递特征的直接结构和功能证据。在此，通过流感病毒 (NP44)、人类免疫缺陷病毒 (RT313) 和 (MTB) 的 T 细胞表位的复合物的晶体结构测定和热稳定性测量，证明了 HLA-A30:01 和 -A30:03 的肽呈递的分子基础。在与 HIV 肽 RT313 结合时，HLA-A30:01 和 -A30:03 的 PΩ-Lys 锚定模式与 A3 超型中的 HLA-A11:01 相似。然而，HLA-A30:03 而不是 -A30:01 也显示与 HLA01:01 有利的肽 NP44 结合，但具有特定的结构构象。因此，与我们之前的理解不同，HLA-A30:01 和 -A30:03 具有特定的肽结合特征，这可能导致它们具有不同的超型特征结合肽基序。此外，我们还发现 F 口袋中的残基 77 是 HLA-A30:01 和 -A30:03 发散性肽呈递特征的关键残基之一。在 HLA-A30:01 和 HLA-A30:03 之间交换残基 77 会改变它们呈现的肽谱。我们的结果为在流行的 HLA 超型人群中筛选病毒和肿瘤特异性肽提供了重要建议，用于疫苗开发和免疫干预。
