Negative Signalling by Killer Ig-like Receptors

描述(申请人提供)：杀伤细胞Ig样受体(KIR)在人类的自然杀伤(NK)细胞和一些T细胞上表达。KIR的配体是I类主要组织相容性复合体(MHC-I)蛋白，表达于体内几乎每个细胞上。KIR对正常靶细胞上MHC-I的识别传递了一个负面信号，该信号抑制了激活事件并抑制了NK细胞的攻击。某些肿瘤细胞和病毒感染细胞可以下调表面MHC-I，以逃避细胞溶解T细胞的检测。然而，当NK细胞遇到这样的突变细胞时，缺乏KIR的参与会触发针对异常靶点的特异性裂解和细胞因子释放。 大量证据表明，蛋白酪氨酸磷酸酶(PTP)，SHP-1，是KIR抑制的一个组成部分。SHP-1被招募到KIR的磷酸化细胞质结构域。然而，SHP-1介导负信号的分子机制尚不清楚，普遍认为SHP-1介导所有抑制功能的观点可能过于简单化。我们的证据还清楚地表明，一种名为SHP-2的相关PTP参与了KIR的负面信号传递。我们认为SHP-1和SHP-2对KIR的作用是不同的，它们可能通过不同的分子机制介导抑制作用。识别每个PTP干扰NK细胞激活途径的特定点应该有助于描绘有希望的分子靶点，以设计治疗策略，有益地操纵NK细胞和其他淋巴细胞的抗肿瘤和抗病毒反应。 我们未来的研究将通过解决以下具体目标来确定SHP-1和SHP-2在KIR负信号中的作用： 1)SHP-1和SHP-2向KIR募集的动力学表征 2)确定SHP-1和SHP-2在抑制KIR中的功能作用 3)激酶在KIR抑制功能中作用的表征

DESCRIPTION (provided by applicant): Killer Cell Ig-like Receptors (KIR) are expressed on natural killer (NK) cells and some T cells in humans. The ligands for KIR are class I major histocompatibility complex (MHC-I) proteins expressed on virtually every cell in the body. KIR recognition of MHC-I on a normal target cell transduces a negative signal that suppresses activation events and restrains NK cells from attacking. Certain tumor cells and virus-infected cells can down regulate surface MHC-I to escape detection by cytolytic T cells. When an NK cell encounters such a mutant cell, however, the lack of KIR engagement triggers specific lysis and cytokine release toward the abnormal target. Substantial evidence implicates the protein tyrosine phosphatase (PTP), SHP-1, as a component of KIR inhibition. SHP-1 is recruited to the phosphorylated cytoplasmic domain of KIR. The molecular mechanism by which SHP-1 mediates negative signalling is unclear, however, and the prevailing view that SHP-1 mediates all inhibitory function is likely too simplistic. Our evidence clearly also implicates a related PTP, named SHP-2, in negative signalling through KIR. We propose that SHP-1 and SHP-2 are differentially recruited to KIR and that they can mediate inhibition through distinct molecular mechanisms. Identification of specific points at which each PTP disrupts NK cell activation pathways should help to delineate promising molecular targets for designing therapeutic strategies to beneficially manipulate anti-tumor and anti-viral responses by NK cells and other lymphocytes. Our future studies will define the roles of SHP-1 and SHP-2 in negative signalling through KIR by addressing the following specific aims: 1) Characterization of the kinetics of SHP-1 and SHP-2 recruitment to KIR 2) Establishment of the functional roles for SHP-1 and SHP-2 in KIR inhibition 3) Characterization of the roles of kinases in KIR inhibitory function