Role of SHIP in NK Cell Biology

描述(申请人提供)：在过去的四年里，这笔赠款使我们取得了几项新的进展，包括证明含有SH2的肌醇磷酸酶(SHIP)在NK细胞的生物学、移植物抗宿主病(GvHD)和异基因骨髓(BM)移植的排斥反应中发挥关键作用。(1-5)我们发现SHIP小鼠的NK受体(NKRR)高度中断，某些NK受体(NKR)主导SHIP-/-NK细胞的功能。此外，SHIP-/-NK细胞中占优势的受体亚群可能会随着自身配体的等位基因差异而变化，如MHC-I类分子。SHIP缺陷所产生的“受体优势”反过来会损害细胞溶解功能，提示了NK功能障碍和免疫缺陷的新机制。综上所述，我们的研究表明，SHIP调节感知自身配体的NKR信号通路，SHIP的作用是阻止一个或几个NK NKR主导NKRR。(1，4，5)我们假设SHIP通过控制NK细胞亚群的生存和增殖(间接影响)或NKR表达(直接影响)的信号通路来调节NKRR。根据我们迄今取得的进展，这项修订后的续期申请已调整为三个目标。在目标1和目标2中，我们将在分子术语中定义调节小鼠NKRR所需的信号通路和SHIP组件。修订后的目标3已重新集中在分子方面，以定义为什么关键的NK细胞溶解功能会因船体缺乏而改变。这一更新应用将在以下具体目标中进行：目标1：定义自配体/受体对，以及招募到它们的信号蛋白，这是通过SHIP调节NKRR所需的。目标2：定义因船舶缺陷而导致NKRR中断的效应器通路。目的3：明确Ship-/-NK细胞功能受损的机制。

DESCRIPTION (provided by applicant): Over the last four years this grant has enabled us to make several novel advances including the demonstration that the SH2-containing Inositol Phosphatase (SHIP) plays a pivotal role in the biology of NK cells, Graft-Versus-Host Disease (GvHD) and rejection of allogeneic bone marrow (BM) grafts.(1-5) We find that the NK receptor repertoire (NKRR) of SHIP mice is highly disrupted with certain NK receptors (NKR) dominating the repertoire of SHIP-/- NK cells. Moreover the subset of receptors that becomes dominant in SHIP-/- NK cells can vary with allelic differences in self ligands such as MHC class I. The "receptor dominance" created by SHIP-deficiency in turn compromises cytolytic function suggesting a novel mechanism for NK dysfunction and immune deficiency. In aggregate our studies indicate SHIP regulates NKR signaling pathways that sense self ligands and that SHIP'S role is to prevent one or a few NK NKR from dominating the NKRR.(1,4,5) We hypothesize then that SHIP regulates the NKRR through signaling pathways that control survival and proliferation of NK cell subsets (indirect effects) or NKR expression (direct effects). Based on our progress to date this revised renewal application has been restructured as three aims. In Aims 1 and 2 we will define in molecular terms the signaling pathways and components of SHIP required for regulation of the murine NKRR. The revised Aim 3 has been refocused to define in molecular terms why key NK cytolytic functions are altered by SHIP-deficiency. This renewal application will be pursued in the following specific aims: Aim 1: Define self-ligand/receptor pairs, and signaling proteins recruited to them, required for regulation of the NKRR by SHIP. Aim 2: Define effector pathways altered by SHIP-deficiency that lead to NKRR disruption. Aim 3: Define the mechanisms responsible for compromised function of SHIP-/- NK cells.