A long N-terminal-extended nested set of abundant and antigenic major histocompatibility complex class I natural Ligands from HIV envelope protein
A long N-terminal-extended nested set of abundant and antigenic major histocompatibility complex class I natural Ligands from HIV envelope protein
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DOI：
10.1074/jbc.m512263200
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发表时间：
2006-03-10
影响因子：
4.8
通讯作者：
Del Val, M
中科院分区：
文献类型：
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作者：
Samino, Y;López, D;Del Val, M
病毒抗原与主要组织相容性复合体（MHC）I类分子复合，被感染细胞上的细胞毒性T淋巴细胞识别。用合成肽进行的测定鉴定了常用于疫苗的最佳MHC I类配体。然而，当分析天然肽时，发现更复杂的混合物，包括在结合位点中间凸出或具有羧基延伸的长肽，反映了抗原加工途径中缺乏对羧肽酶的暴露。相比之下，前体肽暴露于广泛的胞质氨肽酶活性，只有不到1%的生存，只有进一步修剪在内质网。我们在这里展示了一个突出的例子，嵌套的至少三个高度抗原性和类似丰富的天然MHC I类配体，15，10和9个氨基酸的长度，来自一个单一的人类免疫缺陷病毒gp 160表位。因此，抗原加工产生了丰富的可能的配体库，MHC I类分子可以从中选择。天然肽组包括具有前所未有的6个N-末端残基的15个残基长的肽，其最有可能延伸出MHC I类结合沟。该15-mer是已知被细胞毒性T淋巴细胞识别的最长的天然肽，并且令人惊讶地在活细胞中被保护免于氨肽酶修剪。
Viral antigens complexed with major histocompatibility complex (MHC) class Imolecules are recognized by cytotoxic T lymphocytes on infected cells. Assays with synthetic peptides identify optimal MHC class I ligands often used for vaccines. However, when natural peptides are analyzed, more complex mixtures including long peptides bulging in the middle of the binding site or with carboxyl extensions are found, reflecting lack of exposure to carboxypeptidases in the antigen processing pathway. In contrast, precursor peptides are exposed to extensive cytosolic aminopeptidase activity, and fewer than 1% survive, only to be further trimmed in the endoplasmic reticulum. We show here a striking example of a nested set of at least three highly antigenic and similarly abundant natural MHC class I ligands, 15, 10, and 9 amino acids in length, derived from a single human immunodeficiency virus gp160 epitope. Antigen processing, thus, gives rise to a rich pool of possible ligands from which MHC class I molecules can choose. The natural peptide set includes a 15-residue-long peptide with unprecedented 6 N-terminal residues that most likely extend out of the MHC class I binding groove. This 15-mer is the longest natural peptide known recognized by cytotoxic T lymphocytes and is surprisingly protected from aminopeptidase trimming in living cells.