Human transporters associated with antigen processing (TAPs) select epitope precursor peptides for processing in the endoplasmic reticulum and presentation to T cells.
Human transporters associated with antigen processing (TAPs) select epitope precursor peptides for processing in the endoplasmic reticulum and presentation to T cells.
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DOI：
10.1084/jem.190.9.1227
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发表时间：
1999-11-01
期刊：
影响因子：
--
通讯作者：
van Endert PM
中科院分区：
文献类型：
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作者：
Lauvau G;Kakimi K;Niedermann G;Ostankovitch M;Yotnda P;Firat H;Chisari FV;van Endert PM
通过主要组织相容性复合体（MHC）I类分子的抗原呈递需要通过与抗原加工相关的转运蛋白（TAP）提供肽，所述转运蛋白以物种特异性方式以及在大鼠中以等位基因特异性方式选择底物。TAPs和MHC对啮齿动物细胞中COOH末端肽残基的偏好之间的冲突强烈降低了MHC I类抗原呈递的效率。虽然人TAP是相对允许的，但已知人组织相容性白细胞抗原I类分子的一些肽配体具有非常低的TAP亲和力;这些体外发现对细胞抗原呈递的意义尚不清楚。我们研究了两个自然免疫显性病毒抗原表位提出的HLA-A2显示非常低的亲和力，人类TAP。低TAP亲和力排除了最小的表位进入内质网（ER）和装配HLA-A2在体外，以及由小基因表达细胞的细胞毒性T淋巴细胞的介绍。然而，具有更高TAP亲和力的NH 2-末端而不是COOH-末端延伸的表位变体在体外组装并以高效率呈递给细胞毒性T淋巴细胞。因此，人TAP可以影响表位选择并限制表位前体进入ER。一组病毒表位的TAP亲和力分析表明，TAP选择前体可能是HLA-A2呈递表位的常见现象。我们还分析了HLA-A2-洗脱肽minigene表达细胞，并表明，一个NH 2-末端延伸的变体与低A2结合亲和力经历ER加工，而另一个具有高亲和力的未修饰。因此，先前报道的ER中的氨肽酶活性也可以作用于TAP易位肽。
Antigen presentation by major histocompatibility complex (MHC) class I molecules requires peptide supply by the transporters associated with antigen processing (TAPs), which select substrates in a species- and, in the rat, allele-specific manner. Conflicts between TAPs and MHC preferences for COOH-terminal peptide residues in rodent cells strongly reduce the efficiency of MHC class I antigen presentation. Although human TAP is relatively permissive, some peptide ligands for human histocompatibility leukocyte antigen class I molecules are known to possess very low TAP affinities; the significance of these in vitro findings for cellular antigen presentation is not known. We studied two naturally immunodominant viral epitopes presented by HLA-A2 that display very low affinities for human TAP. Low TAP affinities preclude minimal epitope access to the endoplasmic reticulum (ER) and assembly with HLA-A2 in vitro, as well as presentation by minigene-expressing cells to cytotoxic T lymphocytes. However, NH2-terminally but not COOH-terminally extended epitope variants with higher TAP affinities assemble in vitro and are presented to cytotoxic T lymphocytes with high efficiency. Thus, human TAP can influence epitope selection and restrict access to the ER to epitope precursors. Analysis of TAP affinities of a panel of viral epitopes suggests that TAP selection of precursors may be a common phenomenon for HLA-A2–presented epitopes. We also analyzed HLA-A2–eluted peptides from minigene-expressing cells and show that an NH2-terminally extended variant with low A2 binding affinity undergoes ER processing, whereas another with high affinity is presented unmodified. Therefore, the previously reported aminopeptidase activity in the ER can also act on TAP-translocated peptides.