Role of SHIP in Control of NK Cell Function

描述(由申请人提供)：我们发现含有SH2-的 肌醇磷酸酶(SHIP)在确定抑制作用中起着至关重要的作用 体内NK细胞谱系。我们小组支持的四个主要发现 这一假设：(1)SHIP在体内被招募到Ly49A和Ly49C上，(2)SHIP在体内被招募到Ly49A和Ly49C P13K的85kD调节亚基在体内被招募到Ly49A， (3)Akt在体内Ship-/-NK细胞中具有结构性活性；(4)Akt的一个亚群 共表达Ly49A和Ly49C的NK细胞在成人NK细胞亚群中占主导地位 在船-/-老鼠身上。Ly49A和Ly49C可与自身MHC配体相互作用 Ship-/-小鼠，但也有其他MHC单倍型的配体。这个乱七八糟的NK 随着SHIP-/-小鼠的失败，抑制曲目具有深远的功能后果 排斥完全组织不相容的骨髓移植。令人惊讶的是，我们发现 与野生型相比，Ship-/-小鼠的存活率显著提高 移植完全组织不相容的骨髓后产仔。这些 研究结果表明，船舶在限制人类健康的两个过程中发挥着关键作用 组织不合骨髓移植的成功：移植物排斥反应和 移植物抗宿主病。我们现在提议确认并延长我们最初的 观察以更好地了解Ship如何塑造NK细胞 抑制曲目并更好地了解这对骨髓的影响 跨越主要组织相容性障碍的移植。具体来说，我们会： (1)确定SHIP影响NK抑制的机制 谱系，(2)确定一种“自我限制”的NK抑制谱系 改变NK细胞对激活受体的反应能力和(3) 确定移植物排斥反应和取消移植物抗宿主病失败的机制 在SH1P-/-小鼠异基因骨髓移植过程中。

DESCRIPTION (provided by the applicant): We find that the SH2-containing Inositol Phosphatase (SHIP) plays a crucial role in defining the inhibitory repertoire of NK cells in vivo. Four key findings made by our group support this hypothesis: (1) SHIP is recruited to both Ly49A and Ly49C in vivo, (2) the 85kD regulatory subunit of P1-3-Kinase (P13K) is recruited to Ly49A in vivo, (3) Akt is constitutively active in SHIP-/- NK cells in vivo and (4) a subset of NK cells that co express Ly49A and Ly49C dominates the adult NK compartment in SHIP-/- mice. Ly49A and Ly49C can interact with self MHC ligands in our SHIP-/- mice, but also ligands of other MHC haplotypes. This promiscuous NK inhibitory repertoire has profound functional consequences as SHIP-/- mice fail to reject fully histo-incompatible marrow grafts. Strikingly, we find that survival of SHIP-/- mice is dramatically enhanced relative to wild-type littermates following transplantation of fully histo-incompatible marrow. These findings demonstrate a critical role for SHIP in two processes that limit the success of histo-incompatible marrow transplantation: graft rejection and graft-vs.-host disease. We now propose to confirm and extend our initial observations to gain a better understanding of how SHIP shapes the NK cell inhibitory repertoire and to better understand how this impacts marrow transplantation across major histocompatibility barriers. Specifically we will: (1) Determine the mechanism by which SHIP influences the NK inhibitory repertoire, (2) Determine whether a "self-restricted" NK inhibitory repertoire alters the ability of NK cells to respond to activating receptors and (3) Determine the mechanism for failure of graft rejection and abrogated GVHD during allogeneic BMT in SH1P-/- mice.