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并根除感染的病毒 或异常的靶细胞。他们不断地扫描这些细胞的表面，寻找 会表明肿瘤感染或改变。NK细胞受体被激活 通过与靶细胞结合，表达的配体可以激活或抑制NK细胞。 抑制配体的结合阻止了NK细胞的激活，从而使健康的 牢房安然无恙。然而，一旦感染，激活的配体现在就被表达出来 通过靶细胞，导致NK细胞的激活，直接杀死感染者 手机。由于病毒或肿瘤可以主动阻止活化配体在体内的表达 为了逃避NK细胞的检测和杀伤，我们提议破坏与 通过改变抑制配体的结构来抑制受体。这又反过来 解除NK细胞抑制的刹车，导致NK细胞的激活和杀伤。我们的 这一策略是建立在我们最近的发现基础上的，即某些肽结合并改变结构 一类被称为主要组织相容性(MHC)I类分子的配体 激活抑制性杀伤免疫球蛋白受体(KIRS)。通过阻止相互作用 在这两个细胞表面表达的蛋白质之间，我们建议以其他方式重新激活 抑制NK细胞。在这项建议中，我们将研究这种结构变化的普遍性。 整个MHC I分子家族，并测试NK细胞的激活 在基于细胞的体外试验中设计了多肽。

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.