Negative Signalling by Killer Ig-like Receptors

描述（由申请人提供）：杀伤细胞Ig样受体（KIR）在人体的自然杀伤（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，其在体内几乎每个细胞上表达。正常靶细胞上MHC-I的KIR识别转导抑制活化事件并抑制NK细胞攻击的负信号。某些肿瘤细胞和病毒感染的细胞可以下调表面MHC-I以逃避溶细胞性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接合触发特异性裂解和细胞因子向异常靶释放。 大量证据表明蛋白酪氨酸磷酸酶（PTP），SHP-1，作为KIR抑制的一个组成部分。SHP-1被募集到KIR的磷酸化胞质结构域。然而，SHP-1介导负信号的分子机制尚不清楚，并且SHP-1介导所有抑制功能的流行观点可能过于简单化。我们的证据清楚地表明，一个相关的PTP，命名为SHP-2，通过KIR的负信号。我们建议，SHP-1和SHP-2差异招募KIR，他们可以通过不同的分子机制介导抑制。鉴定每个PTP破坏NK细胞活化途径的特定点应有助于描绘有希望的分子靶点，用于设计治疗策略以有利地操纵NK细胞和其他淋巴细胞的抗肿瘤和抗病毒应答。 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在通过KIR的负信号传导中的作用： 1)SHP-1和SHP-2向KIR募集的动力学表征 2)SHP-1和SHP-2在KIR抑制中的功能作用的确立 3)激酶在KIR抑制功能中的作用的表征

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