Pl 3-kinase gamma & T cell-mediated anti-viral responses

PL 3-激酶γ

• 批准号: 7121503
• 负责人: YOJI SHIMIZU
• 金额: $ 28.49万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7121503
• 关键词: T lymphocyte; cell migration; cellular polarity; chemokine; dendritic cells; flow cytometry; homeostasis; immune response; immunoregulation; inflammation; integrins; phosphatidylinositol 3 kinase; protein isoforms; tissue /cell culture; vaccinia virus

DESCRIPTION (provided by applicant): Chemokine-dependent migration of lymphocytes and dendritic cells (DCs) into specific anatomic compartments is essential to optimal T cell immune responses against foreign pathogens. The p110? isoform of the phosphatidyolinositol 3-kinase (PI 3-K) family of lipid kinases is activated by chemokine receptors and other G protein coupled receptors. Lipid products produced by PI 3-K are essential in forming polarized morphologies necessary for directional cell migration and PI 3-K can regulate chemokine-dependent integrin activation. Neutrophils and macrophages from mice deficient in poly exhibit impaired migration to multiple chemotactic stimuli. While p110gamma -/- mice also exhibit impaired CDS T cell anti-viral responses and CD4 T cell-dependent antibody responses, naive T cell migration both in vitro and in vivo is not dependent on p110gamma. However, migration of p110gamma -/- effector T cells into inflammatory sites is dramatically impaired, and p110gamma -/- mice have reduced numbers of DCs in secondary lymphoid organs. Thus, we propose that p110gamma regulates T cell immune responses by specifically regulating DC trafficking into secondary lymphoid organs that is critical for naive T cell priming, and the subsequent migration of effector T cells into inflammatory sites. In Aim 1, we will define the role that p110gamma plays in chemokine-dependent integrin activation and cell polarization on effector T cells. In Aim 2, we will utilize adoptive transfer approaches with wild-type and p110gamma -/- mice to determine the function of p110gamma on CD4 T cell activation in vivo, chemokine-dependent migration of activated T cells in lymph nodes and into non-lymphoid tissue, and DC trafficking and function. In Aim 3, we will define the role of p110gamma in regulating the activation and migration of CDS T cells in response to vaccinia virus. These studies will provide important new insights into the mechanism by which p110gamma regulates T cell-specific immune responses via regulation of T cell and DC migration. Defining the function of p110gamma in regulating homeostatic versus inflammatory trafficking in vivo is critical to the potential utility of p110gamma as an anti-inflammatory drug target. Finally, these studies will provide new insights into T cell responses to vaccinia, which will be critical to the development of more effective smallpox vaccines that have fewer adverse effects.

描述（由申请人提供）：淋巴细胞和树突状细胞 (DC) 趋化因子依赖性迁移至特定的解剖区室对于针对外来病原体的最佳 T 细胞免疫反应至关重要。 p110？脂质激酶磷脂酰肌醇 3-激酶 (PI 3-K) 家族的亚型由趋化因子受体和其他 G 蛋白偶联受体激活。 PI 3-K 产生的脂质产物对于形成定向细胞迁移所需的极化形态至关重要，并且 PI 3-K 可以调节趋化因子依赖性整合素激活。缺乏多聚的小鼠的中性粒细胞和巨噬细胞对多种趋化刺激的迁移能力受损。虽然 p110gamma -/- 小鼠也表现出受损的 CDS T 细胞抗病毒反应和 CD4 T 细胞依赖性抗体反应，但体外和体内的幼稚 T 细胞迁移并不依赖于 p110gamma。然而，p110gamma -/- 效应 T 细胞向炎症部位的迁移受到显着损害，并且 p110gamma -/- 小鼠次级淋巴器官中 DC 的数量减少。因此，我们提出 p110gamma 通过特异性调节 DC 运输到次级淋巴器官来调节 T 细胞免疫反应，这对于初始 T 细胞启动以及随后效应 T 细胞迁移到炎症部位至关重要。在目标 1 中，我们将定义 p110gamma 在趋化因子依赖性整合素激活和效应 T 细胞的细胞极化中所起的作用。在目标 2 中，我们将利用野生型和 p110gamma -/- 小鼠的过继转移方法来确定 p110gamma 对体内 CD4 T 细胞激活、活化 T 细胞在淋巴结中趋化因子依赖性迁移和进入非淋巴的功能组织、DC 运输和功能。在目标 3 中，我们将定义 p110gamma 在调节 CDS T 细胞响应痘苗病毒的激活和迁移中的作用。这些研究将为 p110gamma 通过调节 T 细胞和 DC 迁移来调节 T 细胞特异性免疫反应的机制提供重要的新见解。定义 p110gamma 在调节体内稳态与炎症转运方面的功能对于 p110gamma 作为抗炎药物靶点的潜在用途至关重要。最后，这些研究将为 T 细胞对牛痘的反应提供新的见解，这对于开发更有效、副作用更少的天花疫苗至关重要。