Preventing the spontaneous modification of an HLA-A2-restricted peptide at an N-terminal glutamine or an internal cysteine residue enhances peptide antigenicity
Preventing the spontaneous modification of an HLA-A2-restricted peptide at an N-terminal glutamine or an internal cysteine residue enhances peptide antigenicity
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DOI：
10.1097/00002371-200405000-00001
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发表时间：
2004-05-01
影响因子：
3.9
通讯作者：
Slingluff, CL
中科院分区：
文献类型：
--
作者：
Thompson, LW;Hogan, KT;Slingluff, CL
p68衍生肽QIVDVCHDV通过反向免疫学方法鉴定为能够重建由黑素瘤反应性细胞毒性T淋巴细胞（CTL）系VMM 5识别的表位。该肽尚未通过质谱法在细胞表面上明确证明;因此，认为其不适合用于人黑素瘤疫苗。然而，有趣的是，该肽的抗原性受到两个不同残基处的自发修饰的影响。QIVDVCHDV肽的自发修饰可以发生在6位的半胱氨酸残基或N-末端谷氨酰胺残基处，并且这两种修饰都显著影响CTL识别。避免酸性环境可防止N-末端谷氨酰胺残基转化为焦谷氨酸，这种转化可抑制肽与HLA-A2的结合并减少CTL的识别。天冬酰胺取代N-末端谷氨酰胺和丝氨酸取代半胱氨酸显示出增强肽与HLA-A2的结合并增强CTL对肽的识别。这些研究结果表明，一般的战略，以提高抗原性的其他肽含有类似的氨基酸序列。
The p68-derived peptide, QIVDVCHDV, was identified by a reverse immunology approach as capable of reconstituting an epitope recognized by the melanoma-reactive cytotoxic T lymphocyte (CTL) line VMM5. The peptide has not been demonstrated definitively on the cell surface by mass spectrometry; thus, it is not yet considered appropriate for use in human melanoma vaccines. Interestingly, however, the antigenicity of this peptide was affected by spontaneous modifications at two distinct residues. Spontaneous modification of the QIVDVCHDV peptide can occur at the cysteine residue at position 6 or at the N-terminal glutamine residue, and both modifications dramatically affect CTL recognition. Avoidance of an acidic environment prevents the conversion of the N-terminal glutamine residue to pyroglutamic acid, a conversion that inhibits binding of the peptide to HLA-A2 and diminishes recognition by CTLs. Substitution of asparagine for the N-terminal glutamine and substitution of serine for the cysteine were shown to enhance the binding of the peptide to HLA-A2 and to enhance the recognition of the peptide by CTLs. These findings suggest general strategies for enhancing the antigenicity of other peptides containing similar amino acids in their sequence.