Regulation of Lymphocyte Development by HLH Proteins

描述（由申请方提供）：自然杀伤（NK）细胞在对病毒感染的免疫应答和消除应激或转化细胞中发挥重要作用。它们还可以通过产生炎性细胞因子和调节树突状细胞功能来影响适应性免疫应答。它们杀死转化细胞和影响适应性免疫的能力使它们成为肿瘤免疫治疗的有吸引力的候选者。然而，我们对控制NK细胞发育和功能的机制的理解不足以使我们预测NK细胞应答的治疗操作的结果。我的研究重点是了解控制先天性和适应性淋巴细胞发育的分子机制，重点是E蛋白螺旋-环-螺旋转录因子及其拮抗剂Id蛋白。Id 2对NK细胞发育至关重要，但它如何发挥作用以及它是否是适当的NK细胞成熟和功能所需的仍然是难以捉摸的。我们将测试Id 2是成熟（m）NK细胞的终末成熟所需的假设，因此影响NK细胞对病毒感染的应答，从而限制NK细胞群体中的免疫记忆。我们假设Id 2的功能是限制E蛋白的活性，足以抑制其向交替淋巴细胞命运分化的潜力，但允许E蛋白激活mNK细胞亚群中所需的T细胞相关信号蛋白亚群。我们将确定的分子机制的E蛋白，这是抑制Id 2，功能改变的命运和NK细胞系的功能。我们的研究将使我们能够将E蛋白和Id 2的功能置于控制NK细胞发育和功能的转录调节因子的大网络中，并将有助于我们理解治疗干预如何影响NK细胞反应。

DESCRIPTION (provided by applicant): Natural killer (NK) cells play an important role in the immune response to viral infection and in the eradication of stressed or transformed cells. They can also influence adaptive immune responses through production of inflammatory cytokines and modulation of dendritic cell function. Their ability to kill transformed cells and influence adaptive immunity has made them an attractive candidate for tumor immunotherapy. However, our understanding of the mechanisms controlling NK cell development and function are inadequate to allow us to predict the outcome of therapeutic manipulations on NK cell response. My research is focused on understanding the molecular mechanisms controlling innate and adaptive lymphocyte development with an emphasis on the E protein helix-loop-helix transcription factors and their antagonists that Id proteins. Id2 is critical for NK cell developmet but how it functions and whether it is required for proper NK cell maturation and function has remained elusive We will test the hypothesis that Id2 is required for the terminal maturation of mature (m)NK cells and therefore influences the response of NK cells to virus infection thus limiting immunologic memory in the NK cell population. We hypothesize that Id2 functions to limit E protein activity sufficiently to restrain their potential for differentiation toward alterntive lymphocyte fates yet allows E proteins to activate a subset of T cell-associated signaling proteins that are required in a subset of mNK cells. We will determine the molecular mechanism by which the E proteins, which are inhibited by Id2, function to alter the fate and function of NK lineage cells. Our studies will allow us to place the functions of E proteins and Id2 into the largr network of transcriptional regulators that control NK cell development and function and will contribute to our understanding of how therapeutic interventions will influence NK cell responses.