Regulation of Lymphocyte Development by HLH Proteins

描述(由申请人提供)：自然杀伤(NK)细胞在对病毒感染的免疫反应和根除应激或转化细胞方面发挥重要作用。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反应。它们能够杀死转化的细胞并影响获得性免疫，这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了解还不足以使我们能够预测治疗操作对NK细胞反应的结果。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，但它的功能以及它是否对正常的NK细胞成熟和功能是必需的仍是未知的。我们将检验这样一种假设，即Id2是成熟(M)NK细胞最终成熟所必需的，从而影响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，以抑制它们向另一种淋巴细胞命运分化的可能性，但允许E蛋白激活MNK细胞亚群中所需的T细胞相关信号蛋白的子集。我们将确定被Id2抑制的E蛋白改变NK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控因子的更大网络中，并将有助于我们理解治疗干预将如何影响NK细胞的反应。

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.