CD8 immunity to intracellular infection: Control by E-box transcription factors

描述（由申请方提供）：CD 8 + T细胞对细胞内病原体（如细菌、病毒和原生动物寄生虫）的应答是宿主耐药性的重要组成部分。该提案利用细菌、单核细胞增生李斯特菌和牛痘病毒的实验传染病模型来解决关于宿主CD 8 + T细胞免疫应答对生物恐怖主义的潜在微生物剂的问题。 我们已经发现E蛋白转录因子及其抑制剂Id 2调节CD 8 + T细胞对细胞内病原体的应答，这是这些蛋白质的新功能。我们的目标是在分子水平上了解这个转录调节因子家族如何影响CD 8 + T细胞的活化、增殖、分化和存活，因为它们从幼稚细胞转变为效应细胞再转变为记忆细胞。虽然已知E蛋白在造血和淋巴细胞发育期间调节许多关键发育检查点、谱系定型、增殖和存活，但这些重要蛋白在成熟T细胞中的功能尚未探索。 我们假设在免疫应答过程中CD 8 + T细胞的激活和随后记忆细胞的产生涉及E蛋白转录靶点的调节。为了深入了解调节基因表达的特定E蛋白转录因子，在CD 8 + T细胞应答过程中受其活性调节的基因以及抑制其活性如何调节记忆T细胞形成，我们提出：目的1：确定哪些E蛋白调节体内CD 8 + T细胞应答。我们将检查E2 A，E2-2和HEB缺陷型T细胞的免疫应答，以及这些蛋白质在单核细胞增生李斯特菌和牛痘病毒感染期间的DNA结合活性。目的2：研究体内CD 8 + T细胞抗感染免疫应答过程中E蛋白转录因子调控的分子通路。目标3：建立Id 2-报告基因小鼠系以确定免疫应答期间的Id 2表达模式，并确定表达Id 2的效应T细胞是否为记忆T细胞的前体。

DESCRIPTION (provided by applicant): The CD8+ T cell response to intracellular pathogens such as bacteria, viruses and protozoan parasites is an essential component of host resistance. This proposal utilizes experimental infectious disease models of bacteria, Listeria monocytongenes, and Vaccinia virus to address questions about the host CD8+ T cell immune response against potential microbial agents of bioterrorism. We have discovered that E protein transcription factors and their inhibitor, Id2, regulate the CD8+ T cell response to intracellular pathogens, which is a novel function for these proteins. It is our goal to understand at a molecular level how this family of transcriptional regulators influences the activation, proliferation, differentiation and survival of CD8+ T cells as they transition from naove to effector to memory cells. While the E proteins are known to regulate many key developmental check-points, lineage commitment, proliferation and survival during hematopoiesis and lymphocyte development, the function of these important proteins is unexplored in the mature T cell. We hypothesize that the activation of CD8+ T cells and subsequent generation of memory cells during the immune response involves the regulation of E protein- transcriptional targets. To gain insight into the specific E protein-transcription factors that regulate gene expression, the genes which are regulated by their activity during the CD8+ T cell response and how the inhibition of their activity regulates memory T cell formation, we propose to: Aim 1: Determine which E proteins regulate the in vivo CD8+ T cell response. We will examine the immune response by E2A, E2-2 and HEB-deficient T cells and the DNA-binding activity of each of these proteins during infection with Listeria monocytogenes and Vaccinia virus. Aim 2: Identify the molecular pathways controlled by E protein-transcription factors during the in vivo CD8+ T cell immune response to infection. Aim 3: Create an Id2-reporter mouse line to define the Id2 expression pattern during the immune response and determine if Id2 expressing effector T cells are the precursors to memory T cells.