Regulation of CD8+ T Cell Homeostatis by IL-4

IL-4 对 CD8 T 细胞稳态的调节

基本信息

批准号：
7744024
负责人：
FRED Douglass FINKELMAN
金额：
$ 38.61万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
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/7744024
关键词：
1-Phosphatidylinositol 3-Kinase Acute Address Adoptive Transfer Allergens Antibiotic Therapy Antibodies Apoptotic Appearance Architecture Asthma B-Lymphocytes Bacteria Bacterial Infections Biological Assay Bromodeoxyuridine CD8B1 gene Cell Count Cells Cellular Immunity Communicable Diseases Complex Data Disease Dose Evaluation Flow Cytometry Hand Head Health Homeostasis Human ITGAM gene Immune Immune system Immunity Infection Infectious Agent Inflammatory Interleukin-13 Interleukin-15 Interleukin-4 Kinetics Label Left Light Liquid substance Lymphocytic choriomeningitis virus Lymphoid Malaria Mature T-Lymphocyte Mediating Memory Modeling Monoclonal Antibodies Mus Organ Physiological Plasmodium Population Principal Investigator Process Production Proliferating Proteins Protozoa Recombinant Cytokines Regulation Regulatory T-Lymphocyte Relative (related person)Research Personnel Schistosoma mansoni Schistosomiasis Screening procedure Signal Pathway Signal Transduction Sorting - Cell Movement Spleen Syndrome System T cell regulation T cell response T-Cell Activation T-Cell Proliferation T-Lymphocyte Techniques Testing Thymus Gland Time Transgenic Mice Virus Virus Diseases allergic airway inflammation base cell type cytokine cytotoxic design follow-up fungus graft vs host disease in vivo killings macrophage mouse model neutrophil perforin prevent programs pyroglyphid reconstitution research study

项目摘要

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）：该建议将研究IL-4 T细胞稳态和免疫力的调节。它将研究：1）IL-4刺激CD8+ T细胞增殖的四个部分假设； 2）IL-4还刺激了非T细胞，以区分抑制活化的CD8+ T细胞的调节细胞； 3）这两个过程的动力学差异会导致IL-4首先增强，然后抑制CD8+ T细胞反应； 4）这些现象在健康和疾病中的CD8+ T细胞稳态中很重要。该假设基于体内小鼠研究，该研究表明：1）IL-4对于正常的CD8+ T细胞稳态至关重要，尤其是记忆CD8+ T细胞稳态； 2）IL-4的生理浓度急性诱导CD8+ T细胞通过部分依赖性STAT6依赖性过程增殖，但更慢地通过完全依赖STAT6的过程来减少CD8+ T细胞的响应和细胞数。抑制与CD11b+ Ly6ghi中性粒细胞的增大，活化活化群体的出现有关，这些抑制剂已被其他研究者与活化的CD8+ T细胞的失活和杀死有关。我们的假设在3个具体目标中解决了。首先评估了IL-4刺激T细胞激活和存活的信号传导要求。它将确定IL-4激活STAT6，STAT5和PI-3K对IL-4的有丝分裂和抗凋亡作用的重要性。它还将研究为什么要维持内存CD8+ T细胞需要IL-4和IL-15。第二个目的解决了调节细胞的IL-4激活。它将识别并表征由IL-4激活的脾细胞，以抑制和杀死活化的CD8+ T细胞。确定激活这些调节细胞所需的IL-4剂量；确定信号通路对它们的激活很重要；确定它们杀死活化的T细胞的机制，并评估其在小鼠模型中的重要性，其中IL-4抑制了细胞毒性移植物与宿主疾病（GVHD）。第三个目的将评估内生生产的IL-4和相关细胞因子IL-13对健康和疾病中CD8+ T细胞稳态的影响。为了评估结果的普遍性，此目标将检查IL-4和IL-13对两种炎症性疾病的小鼠模型中T细胞稳态的影响：过敏性气道炎症（哮喘）和Omann综合征；和三种传染病的小鼠模型：血吸虫病，疟疾和淋巴细胞性绒毛膜炎病毒（LCMV）感染。之所以选择这些模型，是因为它可以提供有关IL-4调节T细胞稳态和免疫力的一些独特信息，并且因为它也可以阐明IL-4调节的疾病率。提出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，体内细胞因子产生和流式细胞仪的测定，以测试我们的假设。这些研究的结果应确定IL-4促进或调节CD8+ T细胞反应的环境，并为IL-4和IL-4拮抗剂的潜在用途提供了一种潜在用途，以扩增或抑制适应性或疾病的CD8+ T细胞反应。但也有助于免疫介导的疾病，例如哮喘。该项目将研究免疫系统产生的蛋白质IL-4如何调节T细胞数量和功能，尤其是记忆CD8+ T细胞在健康和疾病中的数量和功能。这些研究的结果应确定IL-4促进或下调CD8+ T细胞反应的情况，并为人类增加或减少适应性或疾病的CD8+ T细胞反应的潜在使用IL-4和IL-4拮抗剂提供指南。