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Impact of Cysteine Residues on MHC Binding Predictions and Recognition by Tumor-Reactive T Cells
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-06-22 , DOI: 10.4049/jimmunol.1901173
Abraham Sachs 1 , Eugene Moore 2 , Zeynep Kosaloglu-Yalcin 2 , Bjoern Peters 2 , John Sidney 2 , Steven A Rosenberg 1 , Paul F Robbins 3 , Alessandro Sette 2, 4
Affiliation  

Key Points Oxidation of Cys-containing peptides can inhibit MHC binding and T cell responses. Effects of inhibiting oxidation of Cys-containing peptides on binding and recognition are detailed. The availability of MHC-binding prediction tools has been useful in guiding studies aimed at identifying candidate target Ags to generate reactive T cells and to characterize viral and tumor-reactive T cells. Nevertheless, prediction algorithms appear to function poorly for epitopes containing cysteine (Cys) residues, which can oxidize and form disulfide bonds with other Cys residues under oxidizing conditions, thus potentially interfering with their ability to bind to MHC molecules. Analysis of the results of HLA-A*02:01 class I binding assays carried out in the presence and absence of the reducing agent 2-ME indicated that the predicted affinity for 25% of Cys-containing epitopes was underestimated by a factor of 3 or more. Additional analyses were undertaken to evaluate the responses of human CD8+ tumor-reactive T cells against 10 Cys-containing HLA class I–restricted minimal determinants containing substitutions of α-aminobutyric acid (AABA), a cysteine analogue containing a methyl group in place of the sulfhydryl group present in Cys, for the native Cys residues. Substitutions of AABA for Cys at putative MHC anchor positions often significantly enhanced T cell recognition, whereas substitutions at non-MHC anchor positions were neutral, except for one epitope where this modification abolished T cell recognition. These findings demonstrate the need to evaluate MHC binding and T cell recognition of Cys-containing peptides under conditions that prevent Cys oxidation, and to adjust current prediction binding algorithms for HLA-A*02:01 and potentially additional class I alleles to more accurately rank peptides containing Cys anchor residues.

中文翻译:

半胱氨酸残基对 MHC 结合预测和肿瘤反应性 T 细胞识别的影响

关键点 含半胱氨酸肽的氧化可抑制 MHC 结合和 T 细胞反应。详细介绍了抑制含半胱氨酸肽氧化对结合和识别的影响。MHC 结合预测工具的可用性在指导旨在确定候选目标 Ags 以生成反应性 T 细胞和表征病毒和肿瘤反应性 T 细胞的研究中很有用。然而,对于含有半胱氨酸 (Cys) 残基的表位,预测算法似乎功能不佳,在氧化条件下,半胱氨酸残基会氧化并与其他 Cys 残基形成二硫键,从而可能干扰它们与 MHC 分子结合的能力。HLA-A*02结果分析:在存在和不存在还原剂 2-ME 的情况下进行的 01 I 类结合测定表明,对 25% 的含 Cys 表位的预测亲和力被低估了 3 倍或更多。进行了额外的分析以评估人类 CD8+ 肿瘤反应性 T 细胞对 10 个含有半胱氨酸的 HLA I 类限制性最小决定簇的反应,该最小决定簇包含 α-氨基丁酸 (AABA) 的取代,这是一种含有甲基的半胱氨酸类似物代替Cys中存在的巯基,对于天然Cys残基。在推定的 MHC 锚定位置用 AABA 替代 Cys 通常显着增强 T 细胞识别,而非 MHC 锚定位置的替代是中性的,除了一个表位,这种修饰取消了 T 细胞识别。
更新日期:2020-06-22
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