Department of Oncology, Ludwig Institute for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland;
Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
J Immunol. 2018 Dec 15;201(12):3705-3716. doi: 10.4049/jimmunol.1800914. Epub 2018 Nov 14.
HLA-I molecules bind short peptides and present them for recognition by CD8 T cells. The length of HLA-I ligands typically ranges from 8 to 12 aa, but variability is observed across different HLA-I alleles. In this study we collected recent in-depth HLA peptidomics data, including 12 newly generated HLA peptidomes (31,896 unique peptides) from human meningioma samples, to analyze the peptide length distribution and multiple specificity across 84 different HLA-I alleles. We observed a clear clustering of HLA-I alleles with distinct peptide length distributions, which enabled us to study the structural basis of peptide length distributions and predict peptide length distributions from HLA-I sequences. We further identified multiple specificity in several HLA-I molecules and validated these observations with binding assays. Explicitly modeling peptide length distribution and multiple specificity improved predictions of naturally presented HLA-I ligands, as demonstrated in an independent benchmarking based on the new human meningioma samples.
HLA-I 分子结合短肽并将其呈递给 CD8 T 细胞识别。HLA-I 配体的长度通常在 8 到 12 个氨基酸之间，但在不同的 HLA-I 等位基因中存在变异性。在这项研究中，我们收集了最近的深入 HLA 肽组学数据，包括 12 个新生成的来自人脑膜瘤样本的 HLA 肽组（31896 个独特的肽），以分析 84 个不同的 HLA-I 等位基因的肽长度分布和多重特异性。我们观察到 HLA-I 等位基因具有明显的聚类，具有不同的肽长度分布，这使我们能够研究肽长度分布的结构基础，并从 HLA-I 序列预测肽长度分布。我们进一步在几个 HLA-I 分子中鉴定了多重特异性，并通过结合测定验证了这些观察结果。明确建模肽长度分布和多重特异性提高了对天然呈现的 HLA-I 配体的预测，这在基于新的人脑膜瘤样本的独立基准测试中得到了证明。
