Regulation of CD8+ T Cell Homeostatis by IL-4

IL-4 对 CD8 T 细胞稳态的调节

• 批准号: 7370197
• 负责人: FRED Douglass FINKELMAN
• 金额: $ 39万
• 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 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7370197
• 关键词: 1-Phosphatidylinositol 3-Kinase; 5-(6)-carboxyfluorescein diacetate succinimidyl ester; Address; Apoptotic; Appearance; Asthma; Bacteria; Binding; Biological Assay; Bromodeoxyuridine; CD8B1 gene; Cell Count; Cell Survival; Cell division; Cells; Cellular Immunity; Clonal Expansion; Communicable Diseases; Condition; Cytokine Receptors; Data; Dependence; Development; Disease; Dose; Evaluation; Exposure to; Flow Cytometry; Health; Homeostasis; Human; ITGAM gene; Immune; Immune response; Immune system; Immunity; Infectious Agent; Inflammatory; Interferon Type II; Interleukin-13; Interleukin-15; 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; Numbers; 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 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

DESCRIPTION (provided by applicant): 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 homeostasis 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.T cell-mediated immunity is required to protect people against infectious agents, including most bacteria, viruses, fungi, protozoa, and worms, but also contributes to immune-mediated disorders, such as asthma. This project will study how IL-4, a protein produced by the immune system, regulates T cell numbers and function, especially the numbers and function of memory CD8+ T cells, in health and disease. The results of these studies should identify the circumstances in which IL-4 promotes or downregulates CD8+ T cell responses and provide a guide to the potential use of IL-4 and IL-4 antagonists for increasing or decreasing adaptive or maladaptive CD8+ T cell responses in humans.

描述(由申请人提供)： 这项建议将研究IL-4对T细胞稳态和免疫的调节。它将探讨四个部分的假设：1)IL-4刺激CD8+T细胞增殖；2)IL-4也刺激非T细胞分化为抑制激活的CD8+T细胞的调节性细胞；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细胞的反应；4)这些现象对健康和疾病中CD8+T细胞的动态平衡非常重要。这一假说是建立在小鼠体内研究的基础上的，这些研究表明：1)IL-4对正常的CD8+T细胞稳态，尤其是记忆性CD8+T细胞稳态是必不可少的；2)生理浓度的IL-4通过部分依赖于Stat6的过程强烈地诱导CD8+T细胞的增殖，但通过完全依赖于Stat6的过程来缓慢地减少CD8+T细胞的反应和细胞数量。抑制与CD11b+Ly6Ghi中性粒细胞的扩大和激活有关，其他研究人员已经发现CD11b+Ly6Ghi中性粒细胞与激活的CD8+T细胞的灭活和杀伤有关。我们的假设有三个具体目标。第一个评估IL-4刺激T细胞激活和存活所需的信号。这将决定IL-4激活Stat6、Stat5和PI-3K在IL-4促有丝分裂和抗凋亡作用中的重要性。它还将调查为什么需要IL-4和IL-15来维持记忆中的CD8+T细胞。第二个目标是解决调节细胞的IL-4激活问题。它将识别和表征由IL-4激活的脾细胞以抑制和杀死激活的CD8+T细胞；确定激活这些调节细胞所需的IL-4的剂量；识别对它们激活至关重要的信号通路；识别它们杀死激活的T细胞的机制(S)，并评估它们在IL-4抑制细胞毒性移植物抗宿主病(GVHD)小鼠模型中的重要性。第三个目标将评估内源性产生的IL-4和相关的细胞因子IL-13在健康和疾病中对CD8+T细胞稳态的影响。为了评估我们结果的普适性，这一目的将检验IL-4和IL-13对两种炎症性疾病小鼠模型T细胞稳态的影响：过敏性呼吸道炎症(哮喘)和Omann综合征；以及三种传染病小鼠模型：血吸虫病、疟疾和淋巴细胞性脉络膜脑膜炎病毒(LCMV)感染。之所以选择这些模型，是因为它可以提供一些关于IL-4调节T细胞稳态和免疫的独特信息，也因为它也可以揭示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、单抗、细胞转移系统、CFSE标记、BrdU掺入、体内细胞因子产生的分析和流式细胞术来验证我们的假设。这些研究的结果应该确定IL-4促进或调节CD8+T细胞反应的情况，并为IL-4和IL-4拮抗剂用于放大或抑制人类适应性或非适应性CD8+T细胞反应的潜在用途提供指导。T细胞介导的免疫是保护人们免受包括大多数细菌、病毒、真菌、原生动物和蠕虫在内的传染病的必需的，但也有助于免疫介导性疾病，如哮喘。该项目将研究免疫系统产生的一种蛋白质IL-4如何在健康和疾病中调节T细胞的数量和功能，特别是记忆CD8+T细胞的数量和功能。这些研究的结果应该确定IL-4促进或下调CD8+T细胞反应的情况，并为潜在使用IL-4和IL-4拮抗剂来增加或降低人类适应性或非适应性CD8+T细胞反应提供指导。