Design and evaluation of HLA-A, -B, and -C binding peptides that disrupt inhibitory KIR/MHC interaction and activate NK cells

项目摘要 自然杀伤（NK）细胞是一种免疫细胞，可以非常迅速地检测和根除感染 或异常的靶细胞。他们不断地扫描这些细胞的表面， 表明肿瘤感染或改变。实现NK细胞受体活化 通过结合靶细胞表达的激活或抑制NK细胞的配体。 抑制性配体的接合防止NK细胞活化，从而允许健康的NK细胞活化。 安全离开然而，在感染后，激活配体现在表达 通过靶细胞，导致NK细胞的激活和直接杀死感染者， cell.由于病毒或肿瘤可以积极地阻止活化配体的表达， 为了逃避NK细胞的检测和杀伤，我们建议破坏与NK细胞的结合， 通过改变抑制性配体的结构来抑制抑制性受体。这反过来 消除NK细胞抑制的制动器，导致NK细胞活化和杀伤。我们 我们的策略建立在我们最近发现某些肽结合并改变结构的基础上 一类称为主要组织相容性（MHC）I类分子的配体， 参与抑制性杀伤免疫球蛋白受体（KIR）。通过阻止 在这两种细胞表面表达的蛋白质之间，我们建议重新激活，否则 抑制NK细胞。在本建议中，我们将研究这种结构变化的普遍性 在整个家族的MHC I分子，并测试激活的NK细胞使用 设计的肽在基于细胞的体外测定中。

Project Summary Natural Killer (NK) cells are immune cells that very rapidly detect and eradicate infected or aberrant target cells. They constantly scan the surface of these cells for changes that would indicate infection or alteration by the tumor. NK cell receptor activation is achieved by binding to target cell expressed ligands that either activate or inhibit the NK cell. Engagement of inhibitory ligands prevents NK cell activation, thus allowing the healthy cell to leave unharmed. However, upon infection, activating ligands are now expressed by the target cell, leading to the activation of the NK cell and direct killing of the infected cell. Since viruses or tumors can actively prevent the expression of activating ligands in an effort to evade NK cell detection and killing we propose to disrupt the binding to inhibitory receptors by altering the structure of the inhibitory ligands. This in turn removes the brakes of NK cell inhibition, leading to NK cell activation and killing. Our strategy is built on our recent discovery that certain peptides bind and alter the structure of one class of ligands, termed Major Histocompatibility (MHC) class I molecules that engage inhibitory Killer Immunoglobulin receptors (KIRs). By preventing the interaction between these two cell-surface expressed proteins, we propose to re-activate otherwise inhibited NK cells. In this proposal we will study the universality of this structural change across the entire family of MHC I molecules, and test the activation of NK cells using designed peptides in a cell-based in vitro assay.