Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims MHC class I-presented peptides in vivo and plays an important role in immunodominance
Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims MHC class I-presented peptides in vivo and plays an important role in immunodominance
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DOI：
10.1073/pnas.0603095103
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发表时间：
2006-06-13
影响因子：
11.1
通讯作者：
Rock, KL
中科院分区：
文献类型：
--
作者：
York, IA;Brehm, MA;Rock, KL
CD 8（+）T细胞对与MHC I类分子结合的短肽有应答。虽然大多数抗原蛋白含有许多可以结合MHC 1类的序列，但这些肽中很少有能真正刺激CD 8 + T细胞应答。此外，产生的T细胞应答通常遵循对不同肽的非常可重复的层次结构，原因尚不清楚。我们发现，一个单一的酶，内质网氨肽酶1（ERAP 1），在抗原处理途径的损失导致在病毒感染的免疫优势的层次结构显着的转变，即使当响应的T细胞具有相同的T细胞受体库。在小鼠中，ERAP 1是在内质网中修剪前体肽的主要酶，并且在此过程中，可以产生或破坏抗原肽。因此，当ERAP 1丢失时，对某些病毒肽的免疫应答降低，对其他病毒肽的免疫应答增加，而对其他病毒肽的免疫应答不变。因此，许多表位必须最初作为前体产生，这些前体通常在与I类MHC结合之前被ERAP 1修剪，而其他表位通常被ERAP 1降解为太短而不能与I类MHC结合的长度。此外，肽修剪和由此产生的肽-MHC复合物的丰度是建立免疫优势的主导因素。
CD8(+) T cells respond to short peptides bound to MHC class I molecules. Although most antigenic proteins contain many sequences that could bind to MHC class 1, few of these peptides actually stimulate CD8+ T cell responses. Moreover, the T cell responses that are generated often follow a very reproducible hierarchy to different peptides for reasons that are poorly understood. We find that the loss of a single enzyme, endoplasmic reticulum aminopeptidase 1 (ERAP1), in the antigen-processing pathway results in a marked shift in the hierarchy of immunodominance in viral infections, even when the responding T cells have the same T cell receptor repertoire. In mice, ERAP1 is the major enzyme that trims precursor peptides in the endoplasmic reticulum and, in this process, can generate or destroy antigenic peptides. Consequently, when ERAP1 is lost, the immune response to some viral peptides is reduced, to others increased, and to yet others unchanged. Therefore, many epitopes must be initially generated as precursors that are normally trimmed by ERAP1 before binding to MHC class I, whereas others are normally degraded by ERAP1 to lengths that are too short to bind to MHC class I. Moreover, peptide trimming and the resulting abundance of peptide-MHC complexes are dominant factors in establishing immunodominance.