Peptides/MHC-I complexes and CD8+T cells

描述：(申请人提供)临床和实验证据点 CD8‘T细胞在细胞内免疫防御中的关键作用 病原体。这些病原体中最重要的是那些对艾滋病负有责任的人 大流行、疟疾和肺结核。许多癌细胞的独特蛋白质， 和普恩一样，也可以被认为是细胞内的病原体。至 帮助开发疫苗，促进对这些病原体的防御，我们正在 刺激CD8 T细胞的热休克融合蛋白(HSFP)的研究 回应。HSFP是由重组分枝杆菌(BCG)57 kDa形成的 热休克蛋白，被称为hsp65，在其C末端融合为 合作伙伴“(多肽或大蛋白结构域)。融合伙伴包含 在抗原提呈细胞(树突状细胞)中被切除的多肽序列 并与细胞的I类MHC分子结合，可以激活CD8T细胞。它是 CD8T细胞疫苗的有效性很可能取决于它们的能力 刺激产生足够数量的强大记忆力CD8T 细胞，能够裂解显示极少数同源多肽-MHC的靶细胞 复合体，因为许多感染病毒的细胞和癌细胞的水平很低 MHC-I分子和一些同源多肽的低拷贝数。我们会研究 HSFP是如何被树突状细胞(DC)摄取和蛋白分解的 DC行为的修饰物如何影响这些过程，包括 模式识别受体的双链RNA和配体 细胞。总体目标是帮助提供一个帮助发展的平台 免疫策略导致强大的记忆CD8T细胞产量增加 细胞。

DESCRIPTION: (provided by applicant) Clinical and experimental evidence point to a critical role for CD8' T cells in immune defenses against intracellular pathogens. Foremost among these pathogens are those responsible for the AIDS pandemic, malaria, and tuberculosis. Distinctive proteins of many cancer cells, as well as prions, can also be considered to be intracellular pathogens. To help develop vaccines that promote defenses against these pathogens, we are studying some heat shock fusion proteins (Hsfp) that stimulate CD8 T cell responses. The Hsfp are formed from a recombinant mycobacterial (BCG) 57kDa heat shock protein, called hsp65, fused at its C-terminus with a "fusion partner" (a polypeptide or large protein domain). Fusion partners contain peptide sequences that, when excised in antigen-presenting (dendritic) cells and bound to the cells' class I MHC molecules, can activate CD8 T cells. It is likely that the effectiveness of CD8 T cell vaccines depends upon their ability to stimulate the production of a sufficient number of potent memory CD8 T cells, able to lyse target cells displaying very few cognate peptide-MHC complexes, because many virus-infected cells and cancer cells have low levels of MHC-I molecules and low copy numbers of some cognate peptides. We will study how Hsfp are taken into and proteolytically cleaved by dendritic cells (DC) and how these processes are affected by modifiers of DC behaviour, including double-stranded RNA and ligands for pattern-recognition receptors on these cells. The overall goal is to help provide a platform to aid in the development of immunization strategies leading to increased yields of potent memory CD8 T cells.