Protective CD4+ T cells

保护性 CD4 T 细胞

基本信息

批准号：
8634713
负责人：
Marc Kevin Jenkins
金额：
$ 38万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-15 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8634713
关键词：
Acquired Immunodeficiency Syndrome Antibiotics Antibodies Antigens B-Lymphocytes Bacteria Bacterial Antigens Bacterial Infections Biological Models Body part CD4 Positive T Lymphocytes CD8B1 gene Cell physiology Cells Complex Cryptococcus DNA Defect Development Effector Cell Epithelial Cells Gene Targeting Generations Genus Mycobacterium Helper-Inducer T-Lymphocyte Human Immune response Immune system Immunity Infection Infection Control Infection prevention Ingestion Interferons Interleukin-10 Interleukin-12 Knowledge Lead Ligands Location Lymphocyte Major Histocompatibility Complex Memory Mesentery Methods Microbe Molecular Mus Oral Patients Peptides Phagocytes Phagosomes Play Population Prevalence Problem Solving Regulatory T-Lymphocyte Role Salmonella Salmonella enterica Site Source System T cell response T-Cell Receptor T-Lymphocyte Testing Th1 Cells Tissues Transgenic Organisms Vaccines base cytokine exhaustion extracellular in vivo Model innovation insight killings lymph nodes memory CD4 T lymphocyte microbial pathogen prevent public health relevance tool trafficking vaccine development

项目摘要

DESCRIPTION (provided by applicant): CD4+ T cells play a major role in adaptive immune responses to intracellular and extracellular microbes by regulating the functions of B cells, CD8+ T cells, and phagocytes. However, the prevalence of phagosomal infections caused by Mycobacteria, Salmonella, and Cryptococcus in CD4+ T cell-deficient AIDS patients demonstrates that the most important function of these cells is phagocyte activation. Yet this function is poorly understood, which probably explains why no effective vaccines exist for these pathogens that kill at 2 million people every year. The size of this knowledge gap becomes clear when one considers the odd features of CD4+ T cell-dependent "concomitant immunity", which likely operates for all phagosomal infections. IFN-? producing Th1 cells control the infection within phagocytes at the initial site of infection and prevent it from spreading to other parts of he body. Oddly, however, the Th1 cells never eliminate the microbes from the initial site. Indeed, persistent infection at the original site is required for the Th1 cells to eliminate bacteria from other body sites after a second infection. The regulatory mechanisms that allow Th1 cells to control the infection without eliminating it are not understood. In addition, it is not clear why CD4+ T cell memory is not retained if the original infection is eliminated and why persistent infection does not result in T cell exhaustion. We will use a sensitive peptide: major histocompatibility complex II (p:MHCII) tetramer- based cell enrichment method to study the endogenous CD4+ T cell response to a prototypical persistent phagosomal infection caused by ingestion of Salmonella enterica serovar Typhimuruim (ST) bacteria to gain insight into how protective CD4+ T cells are generated and function. We will test our idea that presentation of p: MHCII complexes exclusively by infected phagocytes drives the generation of IFN-?-producing Th1 effector cells without generating B cell-dependent follicular helper T cells. We will explore the possibility that infected phagocytes at the site of initial infection produce IL-10, which limis their capacity to clear their infection and prevents terminal differentiation of the Th1 cells, locking them in a state where they retain the capacity to multiple protective phagocyte-activating cytokines. We will determine whether the persistently infected IL-10-producing phagocytes in the mesenteric lymph nodes also stimulate bursts of proliferation by Th1 memory cells that periodically circulate through this site to maintain a stable and functional protective population. Accomplishing our specific aims with a robust defined in vivo model system could guide vaccine development against this recalcitrant class of pathogens.

描述（申请人提供）：CD4+T细胞通过调节B细胞、CD8+T细胞和吞噬细胞的功能，在针对细胞内和细胞外微生物的适应性免疫应答中发挥主要作用。然而，CD4+T细胞缺陷的艾滋病患者中分枝杆菌、沙门氏菌和隐球菌引起的吞噬体感染的流行表明，这些细胞最重要的功能是吞噬细胞激活。然而人们对这一功能知之甚少，这可能解释了为什么没有针对这些每年夺去 200 万人死亡的病原体的有效疫苗。当人们考虑到 CD4+ T 细胞依赖性“伴随免疫”的奇怪特征时，这种知识差距的大小就变得清晰起来，这种免疫可能适用于所有吞噬体感染。干扰素-?产生 Th1 细胞在感染最初部位控制吞噬细胞内的感染，并防止其扩散到身体的其他部位。然而奇怪的是，Th1 细胞从来没有从最初的位置消灭微生物。事实上，Th1 细胞需要在原始部位持续感染，才能在第二次感染后消除身体其他部位的细菌。 Th1 细胞控制感染而不消除感染的调节机制尚不清楚。此外，尚不清楚为什么如果消除原始感染，CD4+ T细胞记忆不会保留，以及为什么持续感染不会导致T细胞耗竭。我们将使用敏感肽：主要组织相容性复合体 II (p:MHCII) 四聚体为基础的细胞富集方法来研究内源性 CD4+ T 细胞对摄入肠沙门氏菌伤寒沙门氏菌引起的典型持续吞噬体感染的反应，以获得深入了解保护性 CD4+ T 细胞如何生成和发挥作用。我们将测试我们的想法，即仅由受感染的吞噬细胞呈递 p：MHCII 复合物可驱动产生 IFN-γ 的 Th1 效应细胞的产生，而不产生 B 细胞依赖性滤泡辅助 T 细胞。我们将探讨初始感染部位受感染的吞噬细胞产生 IL-10 的可能性，IL-10 限制了它们清除感染的能力并阻止 Th1 细胞的终末分化，将它们锁定在保留多种保护性吞噬细胞能力的状态-激活细胞因子。我们将确定肠系膜淋巴结中持续感染的产生 IL-10 的吞噬细胞是否也会刺激 Th1 记忆细胞的爆发性增殖，这些细胞定期在该部位循环以维持稳定和功能性的保护群体。通过强大的体内模型系统来实现我们的具体目标可以指导针对这类顽固病原体的疫苗开发。