Regulation of CD8+ T Cell Homeostatis by IL-4

IL-4 对 CD8 T 细胞稳态的调节

• 批准号: 8204960
• 负责人: FRED Douglass FINKELMAN
• 金额: $ 38.22万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204960
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Apoptotic; Appearance; Asthma; Bacteria; Binding; Biological Assay; Bromodeoxyuridine; CD8B1 gene; Cell Count; Cell Proliferation; Cell Survival; Cell division; Cell physiology; Cells; Cellular Immunity; Clonal Expansion; Communicable Diseases; Cytokine Receptors; Data; Dependence; Development; Disease; Dose; Evaluation; Exposure to; Flow Cytometry; Health; Homeostasis; Human; ITGAM gene; Immune; Immune system; Immunity; Infectious Agent; Inflammatory; Interferon Type II; Interleukin-13; Interleukin-15; Interleukin-2; Interleukin-4; Interleukin-7; Kinetics; Label; Light; Lung; Lymphocytic choriomeningitis virus; MHC Class I Genes; Malaria; Mediating; Memory; Modeling; Monoclonal Antibodies; Mus; Myeloid Cells; Neutrophil Activation; Parasites; Parents; Physiological; Population; Process; Production; Proliferating; Proteins; Protozoa; Recombinant Cytokines; Regulation; Research Personnel; Schistosoma mansoni; Schistosomiasis; Signal Pathway; Signal Transduction; Spleen; Syndrome; System; T cell regulation; T cell response; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Testing; Time; Transgenic Mice; Virus; Virus Diseases; airway hyperresponsiveness; allergic airway disease; allergic airway inflammation; arginase; base; cell killing; cytokine; cytotoxic; cytotoxicity; fungus; graft vs host disease; in vivo; killings; macrophage; mouse model; neutrophil; novel; perforin; prevent; receptor; research study; response

This proposal will study IL-4 regulation of T cell homeostasis and immunity. It will investigate the four part hypothesis that: 1) IL-4 stimulates CD8+ T cells to proliferate; 2) IL-4 also stimulates non-T cells to differentiate into regulatory cells that suppress activated CD8+ T cells; 3) differences in the kinetics of these two processes cause IL-4 to first enhance, then suppress CD8+ T cell responses; and 4) these phenomena are important in CD8+ T cell homeostasis in health and disease. This hypothesis is based on in vivo mouse studies that demonstrate that: 1) IL-4 is essential for normal CD8+ T cell homeostasis, especially memory CD8+ T cell homeostasis; and 2) physiological concentrations of IL-4 acutely induce CD8+ T cells to proliferate through a partially Stat6-dependent process but more slowly decrease CD8+ T cell responses and cell number through an entirely Stat6-dependent process. Suppression is associated with the appearance of an enlarged, activated population of CD11b+Ly6Ghi neutrophils, which have been implicated by other investigators in the inactivation and killing of activated CD8+ T cells. Our hypothesis is addressed in 3 specific aims. The first evaluates signaling requirements for IL-4 stimulation of T cell activation and survival. It will determine the importance of IL-4 activation of Stat6, Stat5, and PI-3K for the mitogenic and anti-apoptotic effects of IL-4. It will also investigate why both IL-4 and IL-15 are required to maintain memory CD8+ T cells. The second aim addresses IL-4-activation of regulatory cells. It will identify and characterize the spleen cells activated by IL-4 to suppress and kill activated CD8+ T cells; determine the dose of IL-4 required to activate these regulatory cells; identify the signaling pathways important for their activation; identify the mechanism(s) by which they kill activated T cells, and evaluate their importance in a mouse model in which IL-4 suppresses cytotoxic graft vs. host disease (GVHD). The third aim will evaluate the effects of endogenously-produced IL-4 and a related cytokine, IL-13, on CD8+ T cell homeostasis in health and disease. To allow evaluation of the generalizability of our results, this aim will examine the effects of IL-4 and IL-13 on T cell homeostatsis in mouse models of two inflammatory disorders: allergic airway inflammation (asthma) and Omann's syndrome; and mouse models of three infectious diseases: schistosomiasis, malaria, and lymphocytic choriomeningitis virus (LCMV) infection. Each of these models has been chosen because it can provide some unique information about IL-4 regulation of T cell homeostasis and immunity and because it also can shed light on the disease-relevance of IL-4 regulation. Proposed experiments will be performed in vivo and use transgenic mice, recombinant cytokines, monoclonal antibodies, cell transfer systems, CFSE labeling, BrdU incorporation, assays of in vivo cytokine production and flow cytometry to test our hypothesis. Results of these studies should identify the circumstances in which IL-4 promotes or regulates CD8+ T cell responses and provide a guide to the potential uses of IL-4 and IL-4 antagonists for amplifying or suppressing adaptive or maladaptive CD8+ T cell responses in humans.

该提案将研究 IL-4 对 T 细胞稳态和免疫的调节。它将调查四个部分 假设： 1) IL-4 刺激 CD8+ T 细胞增殖； 2）IL-4也刺激非T细胞分化 进入抑制活化 CD8+ T 细胞的调节细胞； 3）这两个过程的动力学差异 导致 IL-4 首先增强，然后抑制 CD8+ T 细胞反应； 4）这些现象很重要 健康和疾病中的 CD8+ T 细胞稳态。该假设基于小鼠体内研究 证明： 1) IL-4 对于正常 CD8+ T 细胞稳态至关重要，尤其是记忆 CD8+ T 细胞 体内平衡； 2) 生理浓度的 IL-4 通过以下途径急剧诱导 CD8+ T 细胞增殖： 部分依赖 Stat6 的过程，但更缓慢地降低 CD8+ T 细胞反应和细胞数量 一个完全依赖于 Stat6 的过程。抑制与放大、激活的外观有关。 CD11b+Ly6Ghi 中性粒细胞群体，其他研究人员已发现其与失活有关 并杀死活化的 CD8+ T 细胞。我们的假设有 3 个具体目标。第一个评价 IL-4 刺激 T 细胞活化和存活的信号传导需求。它将决定重要性 IL-4 激活 Stat6、Stat5 和 PI-3K，以实现 IL-4 的有丝分裂和抗凋亡作用。它还将 研究为什么需要 IL-4 和 IL-15 来维持记忆 CD8+ T 细胞。第二个目标解决 IL-4-调节细胞的激活。它将识别和表征由 IL-4 激活的脾细胞以抑制 并杀死活化的CD8+ T细胞；确定激活这些调节细胞所需的 IL-4 剂量；确认 对于其激活很重要的信号通路；确定它们杀死激活的 T 的机制 细胞，并评估它们在 IL-4 抑制细胞毒性移植物抗宿主疾病的小鼠模型中的重要性 （移植物抗宿主病）。第三个目标将评估内源产生的 IL-4 和相关细胞因子 IL-13 的作用， 健康和疾病中 CD8+ T 细胞稳态的影响。为了评估我们结果的普遍性，这 目的将检查 IL-4 和 IL-13 对两种炎症小鼠模型中 T 细胞稳态的影响 疾病：过敏性气道炎症（哮喘）和阿曼综合征；和三个小鼠模型 传染病：血吸虫病、疟疾、淋巴细胞性脉络膜脑膜炎病毒（LCMV）感染。每个 选择这些模型的原因是它可以提供一些有关 T 细胞 IL-4 调节的独特信息 细胞稳态和免疫，因为它还可以揭示 IL-4 调节与疾病的相关性。 拟议的实验将在体内进行，并使用转基因小鼠、重组细胞因子、单克隆 抗体、细胞转移系统、CFSE 标记、BrdU 掺入、体内细胞因子产生的测定和 流式细胞术来检验我们的假设。这些研究的结果应确定 IL-4 发挥作用的情况 促进或调节 CD8+ T 细胞反应，并为 IL-4 和 IL-4 的潜在用途提供指导 用于放大或抑制人类适应性或适应不良 CD8+ T 细胞反应的拮抗剂。

项目成果

Sustained IL-4 exposure leads to a novel pathway for hemophagocytosis, inflammation, and tissue macrophage accumulation.

持续的 IL-4 暴露会导致噬血作用、炎症和组织巨噬细胞积累的新途径。

• 发表时间: 2010-10-07
• 影响因子: 20.3
• 作者: Milner, Joshua D;Orekov, Tatyana;Ward, Jerrold M;Cheng, Lily;Torres;Junttila, Ilkka;Sun, Guangping;Buller, Mark;Morris, Suzanne C;Finkelman, Fred D;Paul, William E
• 通讯作者: Paul, William E

Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation.

TH2 炎症的标志是局部巨噬细胞增殖，而不是从血液中招募。

• 发表时间: 2011-06-10
• 作者: Jenkins, Stephen J;Ruckerl, Dominik;Cook, Peter C;Jones, Lucy H;Finkelman, Fred D;van Rooijen, Nico;MacDonald, Andrew S;Allen, Judith E
• 通讯作者: Allen, Judith E