STRUCTURE AND FUNCTION OF PEPTIDE TRANSPORTERS

CD8+T细胞(TCD8+)在病毒控制中的重要作用 感染。TCD8+识别8到10个来自于 病毒蛋白位于病毒感染细胞的胞浆中。这些 多肽是在含有编码为I类分子的复合体中识别的 主要组织相容性复合体(MHC)。在过去的三年里， 发现MHC还编码两个分子，分别称为TAP1和TAP1 TAP2，它似乎能特异性地从胞浆中转运多肽 进入含有I类分子的细胞内隔间。 已发现TAP基因在人类中是多态的，尽管对 比I类分子小得多。这些东西的存在 推测的多肽泵及其多态引发了许多 重要问题：泵在细胞中的位置？做这个 泵会影响I类分子呈现的多肽类型吗？ 泵是否与产生抗原肽的蛋白酶相连？ 在细胞质中吗？这些泵是怎么工作的？有没有个人有 基于TAP基因突变的免疫缺陷？CAN细胞 通过其他机制转运多肽？ 为了帮助确定TAP基因的结构和功能，我们 已经将它们植入牛痘病毒。我们已经证明了一个 编码TAP1的VAc重组产生一个全功能基因，并且 发现这种重组产生的TAP1定位于 糖基化的内质网。我们制作了一个 产生具有功能活性的TAP2的重组蛋白。我们还有 检测抗原转运体的特异性。我们发现 转运体可以运输与CLASS呈递的完全相同的多肽 I分子。我们还检测了人类TAP2基因的表达 在小鼠细胞中对细胞的呈现能力产生不利影响 病毒蛋白转化为TCD8+。我们发现人类TAP2基因的功能 以一种与其对应的老鼠难以区分的方式。最后，我们 已经探索了多肽在细胞中的呈现方式 表达一个或两个TAP基因。

CD8+ T cells (TCD8+ ) play an important role in controlling virus infections. TCD8+ recognize peptides of 8 to 10 residues derived from viral proteins located in the cytosol of virus infected cells. These peptides are recognized in a complex with class I molecules encoded by the major histocompatibility complex (MHC). In the past 3 years it was discovered that the MHC also encodes two molecules, termed TAP1 and TAP2, that seem to specifically transport peptides from the cytosol into the intracellular compartment that contains class I molecules. TAP genes have been found to be polymorphic in humans, although to a far lesser extent than the class I molecules. The existence of these putative peptide pumps and their polymorphism raises a number of important questions: Where in the cells are the pumps located? Do the pumps influence the types of peptides presented by class I molecules? Are the pumps tethered to the proteases that produce antigenic peptides in the cytosol? How do the pumps work? Are there individuals with immune deficiencies based on mutations in the TAP genes? Can cells transport peptides via other mechanisms? To help characterize the structure and function of the TAP genes we have inserted them into vaccinia virus. We have demonstrated that a Vac recombinant encoding TAP1 produces a fully functional gene, and have found that TAP1 produced by this recombinant localizes to the endoplasmic reticulum where it is glycosylated. We produced a recombinant that produces a functionally active TAP2. We have also examined the specificity of the antigen transporters. We found that the transporters can transport the exact peptides presented by class I molecules. Also we examined whether expression of the human TAP2 gene in mouse cells adversely affects the ability of the cells to present viral proteins to TCD8+. We find that the human TAP2 gene functions in a indistinguishable manner from its mouse counterpart. Finally, we have explored the presentation of peptides in cells that fail to express one or both TAP genes.