Protective CD4+ T cells

保护性 CD4 T 细胞

基本信息

批准号：
9228319
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/9228319
关键词：
Acquired Immunodeficiency Syndrome Antibiotics Antibodies Antigens B-Lymphocytes Bacteria Bacterial Antigens Bacterial Infections Biological Models Body part CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell physiology Cells Complex Cryptococcus DNA Defect Development Effector Cell Epithelial Cells Gene Targeting Generations Genus Mycobacterium Helper-Inducer T-Lymphocyte Human Immune system Immunity Infection Infection Control Ingestion Interferon Type II 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 Receptor T-Lymphocyte Testing Th1 Cells Tissues Transgenic Organisms Vaccines adaptive immune response base cytokine exhaustion extracellular in vivo Model innovation insight killings lymph nodes memory CD4 T lymphocyte microbial pathogen prevent public health relevance response 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-γ 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-γ-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（由申请人证明）：CD4+ T细胞在对细胞内和细胞外微生物的适应性免疫反应中起着主要作用。，CD4+ T细胞缺陷的AIDS中的加密辅助是这些细胞的最重要功能是吞噬的功能。而CD4+ T-Cell-Depiantent的操作者则为所有吞噬体感染而产生的“伴随免疫力”。 Th1细胞从未消除原始位点的持续性感染，以使第二次感染后从其他身体部位消除Bactteria。如果消除了原始感染以及为什么持续不导致T细胞疲惫的原因，我们将使用敏感的肽：主要的组织兼容性复合物II（P：MHCII）D来研究内源性CD4+ T细胞对原型吞噬由肠道肠道（ST）细菌引起的感染是如何生成保护剂CD4+ T细胞的，并通过诱导的吞噬细胞发挥作用将探索在初始农产品部位感染的吞噬细胞的吞噬细胞，而在capace中，可以清除感染，并防止其在将capace保留到多重保护性吞噬细胞激活细胞因子的状态的状态下的终极分化。我们将确定在肠系膜淋巴结中持续感染的IL-10产量细胞也刺激了稳定的保护群体。