Determination of a Predictive Cleavage Motif for Eluted Major Histocompatibility Complex Class II Ligands.
Determination of a Predictive Cleavage Motif for Eluted Major Histocompatibility Complex Class II Ligands.
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DOI：
10.3389/fimmu.2018.01795
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发表时间：
2018
影响因子：
7.3
通讯作者：
Peters B
中科院分区：
文献类型：
--
作者：
Paul S;Karosiene E;Dhanda SK;Jurtz V;Edwards L;Nielsen M;Sette A;Peters B
CD4+T细胞在调节免疫反应中起着重要作用。它们是通过识别主要由外源抗原产生的多肽而激活的，这些多肽是通过主要组织相容性复合体(MHC)第二类途径产生的。表位的识别非常重要，为了节省时间和资源，表位的计算预测得到了广泛的应用。虽然已经有算法来预测多肽与MHC II分子的结合亲和力，但没有准确的方法来预测哪些配体是自然抗原处理的结果。我们利用一个由大约14,000个自然处理的配体组成的数据集，通过从MHC II类表达细胞中洗脱出来的多肽的质谱分析来研究序列签名的存在，这些序列签名可能与将呈现的多肽从源抗原中解放出来的切割机制有关。这一分析显示了配体N-端和C-端周围的优先氨基酸，表明了序列特异性的切割偏好。我们利用这些切割基序开发了一种预测自然加工的MHC II配体的方法，并验证了它具有从独立研究中识别配体的预测能力。我们进一步证实，基于切割基序的配体预测可以与MHC结合的预测相结合，并且组合预测具有更好的性能。然而，当试图预测CD4+T细胞表位时，无论是单独预测还是与MHC结合预测结合，基于切割基序的预测都没有显示出预测能力。由于根据CD4+T细胞的反应性确定的表位多肽通常没有明确定义的末端，因此有可能存在基序，但不在映射的表位之外。我们试图在计算上考虑到这一点，但没有显示出任何迹象表明，在具有良好特征的CD4+T细胞表位周围，切割基序的存在增加了。虽然我们尝试将MHC II配体洗脱数据中的切割基序转换为T细胞表位预测的尝试可能不是最优的，但其他可能的解释是切割信号过于稀释而无法检测，或者通过较少用于T细胞表位的抗原处理和呈递途径产生的配体的洗脱数据被丰富。
CD4+ T cells have a major role in regulating immune responses. They are activated by recognition of peptides mostly generated from exogenous antigens through the major histocompatibility complex (MHC) class II pathway. Identification of epitopes is important and computational prediction of epitopes is used widely to save time and resources. Although there are algorithms to predict binding affinity of peptides to MHC II molecules, no accurate methods exist to predict which ligands are generated as a result of natural antigen processing. We utilized a dataset of around 14,000 naturally processed ligands identified by mass spectrometry of peptides eluted from MHC class II expressing cells to investigate the existence of sequence signatures potentially related to the cleavage mechanisms that liberate the presented peptides from their source antigens. This analysis revealed preferred amino acids surrounding both N- and C-terminuses of ligands, indicating sequence-specific cleavage preferences. We used these cleavage motifs to develop a method for predicting naturally processed MHC II ligands, and validated that it had predictive power to identify ligands from independent studies. We further confirmed that prediction of ligands based on cleavage motifs could be combined with predictions of MHC binding, and that the combined prediction had superior performance. However, when attempting to predict CD4+ T cell epitopes, either alone or in combination with MHC binding predictions, predictions based on the cleavage motifs did not show predictive power. Given that peptides identified as epitopes based on CD4+ T cell reactivity typically do not have well-defined termini, it is possible that motifs are present but outside of the mapped epitope. Our attempts to take that into account computationally did not show any sign of an increased presence of cleavage motifs around well-characterized CD4+ T cell epitopes. While it is possible that our attempts to translate the cleavage motifs in MHC II ligand elution data into T cell epitope predictions were suboptimal, other possible explanations are that the cleavage signal is too diluted to be detected, or that elution data are enriched for ligands generated through an antigen processing and presentation pathway that is less frequently utilized for T cell epitopes.
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发表时间：
1997-10-01
期刊：
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影响因子：
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作者：
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发表时间：
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期刊：
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影响因子：
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影响因子：
4.3
作者：
Calis JJ;Maybeno M;Greenbaum JA;Weiskopf D;De Silva AD;Sette A;Keşmir C;Peters B
通讯作者：
Peters B
影响因子：
32.4
作者：
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