Role of SHIP in Control of NK Cell Function

描述（由申请人提供）：我们发现含SH 2的 肌醇磷酸酶（SHIP）在定义抑制性 体内NK细胞库。我们的小组支持得出的四个关键发现 这一假设：（1）SHIP在体内被招募到Ly 49 A和Ly 49 C，（2） P1-3-激酶的85 kD调节亚基（P13 K）在体内被募集到Ly 49 A， (3)Akt在体内SHIP-/- NK细胞中具有组成性活性，以及（4）Akt在SHIP-/- NK细胞中的亚群 共表达Ly 49 A和Ly 49 C的NK细胞占主导地位， SHIP-/-小鼠。Ly 49 A和Ly 49 C可以与自身MHC配体相互作用， SHIP-/-小鼠，但也有其他MHC单倍型的配体。这个滥交的朝鲜 当SHIP-/-小鼠失败时， 排斥组织完全不相容的骨髓移植物令人惊讶的是，我们发现， SHIP-/-小鼠的存活率相对于野生型显著提高 移植完全组织不相容的骨髓后的同窝仔。这些 研究结果表明，船舶在两个过程中发挥着关键作用， 组织相容性骨髓移植成功：移植物排斥反应和 移植物vs.宿主疾病我们现在建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 为了更好地了解这是如何影响骨髓的， 跨越主要组织相容性障碍的移植。具体而言，我们将： (1)确定SHIP影响NK抑制的机制 （2）确定“自限制性”NK抑制性库是否 改变NK细胞对活化受体的反应能力，和（3） 确定移植物排斥失败和废除GVHD的机制 在SH 1 P-/-小鼠的同种异体BMT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.