Regulation of Lymphocyte Development by HLH Proteins

描述（由申请人提供）：自然杀伤（NK）细胞在病毒感染的免疫反应和应激或转化细胞的根除中发挥重要作用。它们还可以通过产生炎症细胞因子和调节树突状细胞功能来影响适应性免疫反应。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一个有吸引力的候选者。然而，我们对控制NK细胞发育和功能的机制的理解还不足以让我们预测NK细胞反应的治疗操作的结果。我的研究重点是了解控制先天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。Id2对NK细胞的发育至关重要，但它是如何起作用的，以及它是否是NK细胞成熟和功能所必需的，我们仍然难以捉摸。我们将验证Id2是成熟(m)NK细胞最终成熟所必需的假设，因此影响NK细胞对病毒感染的反应，从而限制NK细胞群体的免疫记忆。我们假设Id2的功能足以限制E蛋白的活性，以抑制其向其他淋巴细胞分化的潜力，但允许E蛋白激活mNK细胞子集所需的T细胞相关信号蛋白子集。我们将确定被Id2抑制的E蛋白改变NK系细胞命运和功能的分子机制。我们的研究将使我们能够将E蛋白和Id2的功能置于控制NK细胞发育和功能的转录调节因子的更大网络中，并将有助于我们了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.