NETMHCSTAB - predicting stability of peptide-MHC-I complexes; impacts for cytotoxic T lymphocyte epitope discovery
NETMHCSTAB - predicting stability of peptide-MHC-I complexes; impacts for cytotoxic T lymphocyte epitope discovery
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DOI：
10.1111/imm.12160
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发表时间：
2014-01-01
期刊：
影响因子：
6.4
通讯作者：
Nielsen, Morten
中科院分区：
文献类型：
--
作者：
Jorgensen, Kasper W.;Rasmussen, Michael;Nielsen, Morten
主要组织相容性复合体I类(MHC-I)分子在细胞免疫反应中发挥重要作用，向细胞毒性T淋巴细胞(CTL)呈递多肽，使免疫系统能够仔细检查细胞内正在进行的蛋白质生产。20世纪90年代初，多肽-MHC-I(pMHC-I)复合体的免疫原性和稳定性被证明是相关的。当时，测量稳定性既麻烦又耗时，而且只分析了很小的数据集。在这里，我们与以前的研究相比，对这一相当未开发的地区进行了大规模的调查。最近的一项小规模研究表明，与多肽-MHC-I的亲和力相比，pMHC-I复合体的稳定性更能反映CTL的免疫原性。我们在这里扩展了这项研究，分析了总共5509个不同的多肽稳定性测量，涵盖了10个不同的HLAI类分子。人工神经网络被用来构建能够预测pMHC-I复合体半衰期的稳定性预测器。与亲和力匹配的非表位相比，这些预测因子可以预测SYFPEITHI和IEDB的T细胞表位和MHC配体形成明显更稳定的MHC-I复合体。结合稳定性预测和最先进的亲和力预测，NetMHCcons显著提高了识别T细胞表位和配体的性能。对于研究中包括的HLA等位基因，我们可以识别区分稳定和不稳定肽结合的不同亚基，并证明结合基序N端的锚定位置(主要是P2和P3)对稳定的pMHC-I复合体的形成起关键作用。实现该方法的Web服务器可在www.cbs.dtu.dk/services/NetMHCstab上找到。
Major histocompatibility complex class I (MHC-I) molecules play an essential role in the cellular immune response, presenting peptides to cytotoxic T lymphocytes (CTLs) allowing the immune system to scrutinize ongoing intracellular production of proteins. In the early 1990s, immunogenicity and stability of the peptide-MHC-I (pMHC-I) complex were shown to be correlated. At that time, measuring stability was cumbersome and time consuming and only small data sets were analysed. Here, we investigate this fairly unexplored area on a large scale compared with earlier studies. A recent small-scale study demonstrated that pMHC-I complex stability was a better correlate of CTL immunogenicity than peptide-MHC-I affinity. We here extended this study and analysed a total of 5509 distinct peptide stability measurements covering 10 different HLA class I molecules. Artificial neural networks were used to construct stability predictors capable of predicting the half-life of the pMHC-I complex. These predictors were shown to predict T-cell epitopes and MHC ligands from SYFPEITHI and IEDB to form significantly more stable MHC-I complexes compared with affinity-matched non-epitopes. Combining the stability predictions with a state-of-the-art affinity predictions NetMHCcons significantly improved the performance for identification of T-cell epitopes and ligands. For the HLA alleles included in the study, we could identify distinct sub-motifs that differentiate between stable and unstable peptide binders and demonstrate that anchor positions in the N-terminal of the binding motif (primarily P2 and P3) play a critical role for the formation of stable pMHC-I complexes. A webserver implementing the method is available at www.cbs.dtu.dk/services/NetMHCstab.