Lee S P, Thomas W A, Blake N W, Rickinson A B
CRC Institute for Cancer Studies, University of Birmingham, GB.
Eur J Immunol. 1996 Aug;26(8):1875-83. doi: 10.1002/eji.1830260831.
Antigen presentation to CD8+ cytotoxic T lymphocytes (CTL) usually involves proteolytic cleavage of antigen in the cytosol and the delivery of epitope peptides onto major histocompatibility complex class I molecules in the endoplasmic reticulum (ER) via the heterodimeric peptide transporter TAP1/TAP2. In the few exceptional cases where TAP-independent presentation of an endogenously expressed protein has been observed, the epitope-containing domain of the protein either has naturally accessed or has been directed into the ER lumen where it is thought to become susceptible to ER proteases. Here, we describe a novel example of TAP-independent processing involving the Epstein-Barr virus (EBV) latent membrane protein LMP2, a multiple membrane-spanning protein with minimal projection into the ER. Expression of LMP2 in the TAP-T2 cell line, whether from the resident EBV genome or from a recombinant vaccinia virus vector vacc-LMP2, rendered the cells sensitive to recognition by CTL clones specific for two HLA-A2.1-restricted peptide epitopes, LMP2 329-337 or 426-434. Vacc-LMP2-mediated sensitization to lysis required expression of the antigen de novo in T2 cells and was blocked by brefeldin A. In the same experiments, two other EBV-specific CTL epitopes, one derived from LMP2 but restricted through a different HLA allele (A11), the other restricted through A2.1 but derived from a different viral protein (BMLF1), did not display TAP-independent processing. The results are discussed in relation to the unusual topology of LMP2 in the membrane and the position of the epitope peptides within that structure.
向CD8 + 细胞毒性T淋巴细胞（CTL）呈递抗原通常涉及细胞质中抗原的蛋白水解切割，以及通过异二聚体肽转运体TAP1/TAP2将表位肽递送至内质网（ER）中的主要组织相容性复合体I类分子上。在少数观察到内源性表达蛋白不依赖TAP呈递的特殊情况下，该蛋白的含表位结构域要么自然进入内质网腔，要么被引导进入内质网腔，在那里它被认为易受内质网蛋白酶的作用。在这里，我们描述了一个不依赖TAP加工的新例子，涉及爱泼斯坦-巴尔病毒（EBV）潜伏膜蛋白LMP2，这是一种多跨膜蛋白，在内质网中的突出部分最少。LMP2在TAP-T2细胞系中的表达，无论是来自常驻的EBV基因组还是来自重组痘苗病毒载体vacc-LMP2，都使细胞对针对两个HLA-A2.1限制性肽表位LMP2 329-337或426-434的CTL克隆的识别敏感。vacc-LMP2介导的对裂解的敏感性需要T2细胞中抗原的从头表达，并被布雷菲德菌素A阻断。在相同的实验中，另外两个EBV特异性CTL表位，一个来自LMP2但受不同HLA等位基因（A11）限制，另一个受A2.1限制但来自不同的病毒蛋白（BMLF1），没有表现出不依赖TAP的加工。结合LMP2在膜中的异常拓扑结构以及该结构中表位肽的位置对结果进行了讨论。
