Cytotoxic Response to Histocompatibility Antigens

对组织相容性抗原的细胞毒性反应

• 批准号: 7371860
• 负责人: Michael J Bevan
• 金额: $ 39.94万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-06-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7371860
• 关键词: Accounting; Address; Antigen-Presenting Cells; Antigens; Automobile Driving; B-Lymphocytes; Bacteria; Bacterial Infections; CD4 Positive T Lymphocytes; CD8B1 gene; Cell division; Cells; Communicable Diseases; Condition; Cytotoxic T-Lymphocytes; Effector Cell; End Point; Exposure to; Face; Frequencies; Generations; Goals; Grant; Health; Helper-Inducer T-Lymphocyte; Histocompatibility Antigens; Human; Immune system; Immunity; Infection; Infectious Agent; Interleukin-2; Kinetics; Life; Light; Listeria monocytogenes; Lymphocyte; Lymphocytic choriomeningitis virus; Maintenance; Mediating; Memory; Modeling; Mus; Numbers; Pattern; Phase; Point Mutation; Public Health; Research; Role; Role playing therapy; Signal Transduction; Staging; T memory cell; T-Lymphocyte; TNFSF10 gene; Tissues; Upper arm; Vaccination; Viral; Virulent; Virus; Work; base; cell type; cost; cytokine; cytotoxic; desire; follow-up; pathogen; progenitor; programs; research study; response; transcription factor; vaccine delivery

DESCRIPTION (provided by applicant): Vaccination is a cost-effective means of promoting public health. It depends on the ability of the adaptive immune system, comprising T and B lymphocytes, to mount a rapid protective response to a second infection. Cytotoxic T lymphocytes which express the CD8 marker, are of vital importance in the response to many intracellular infectious agents. Our goal is to shed light on the factors that are involved in generating an effective CD8+ T cell response to pathogen and in promoting the differentiation of the primary effector cells into long-lived memory. It has recently become clear that helper T lymphocytes which express the CD4 marker, are critically involved in achieving this desired goal. Even in the face of infection with a virulent pathogenic virus or intracellular bacterium, the CD8 response requires the response of CD4+ T cells. This contribution may be via the activation of antigen presenting cells or via secretion of cytokines, such as IL-2, which may signal directly to the CD8+ T cells. CD4+ T cells are also required for the long term health and maintenance of CD8 memory cells once they are formed. Using infectious agents such as lymphocytic choriomeningitis virus and Listeria monocytogenes to infect mice we will probe the contribution of CD4+ T cells during the priming or vaccination stage and during memory maintenance. Specific Aim 1. To investigate the role of CD4+ T cells in maintaining the numbers, health and function of CD8+ memory T cells after the primary response is over. This entails asking which subset of CD4+ T cells provides the maintenance function, and its underlying basis. We have developed the helper-deficient, HD-/- mouse bearing a point mutation in the transcription factor Th-POK, as an ideal model in which to address these questions. Specific Aim 2. To investigate the factors, such as IL-2 signaling, that are relevant in programming the complete differentiation of pathogen-specific CD8+ T cells into memory cells capable of mounting a robust secondary response to pathogen rechallenge. The goal of vaccination is to generate a pool of memory lymphocytes specific for a pathogen which can protect us for a lifetime. Subsets of T lymphocytes, helpers and killers, must cooperate to achieve protection against many viral and bacterial infections. Our research will shed light on this cooperation for the promotion of long-lived protective immunity. Vaccination against infectious disease is the most cost-effective strategy in promoting human health. Our research is aimed at discovering the conditions that make long-term protection possible following vaccine delivery.

描述（由申请人提供）：疫苗接种是促进公共卫生的一种经济高效手段。这取决于构成T和B淋巴细胞的自适应免疫系统的能力，其对第二种感染的快速保护反应。表达CD8标记的细胞毒性T淋巴细胞在对许多细胞内传染剂的反应中至关重要。我们的目标是阐明在产生有效的CD8+ T细胞对病原体反应以及将主要效应细胞分化为长寿命记忆中的因素。最近很明显，表达CD4标记的辅助T淋巴细胞主要参与实现这一预期目标。即使面对有毒物病毒或细胞内细菌感染的感染，CD8反应也需要CD4+ T细胞的反应。该贡献可以通过激活抗原呈递细胞或通过细胞因子的分泌（例如IL-2）来直接信号向CD8+ T细胞发出信号。 CD4+ T细胞的长期健康和CD8存储单元的维持也是必需的。使用传染剂，例如淋巴细胞绒毛膜炎病毒和单核细胞增生李斯特菌，在启动或疫苗接种阶段以及记忆维持期间，将探测CD4+ T细胞的贡献。具体目的1。研究CD4+ T细胞在主要反应结束后CD8+记忆T细胞的数量，健康和功能中的作用。这需要询问CD4+ T细胞的哪个子集提供维护函数及其基础。我们已经开发了缺乏辅助的HD - / - 小鼠在转录因子TH-POK中的点突变，作为解决这些问题的理想模型。具体目的2。要研究与编程病原体特异性CD8+ T细胞完全分化的因素，这些因素（例如IL-2信号传导）与能够安装对病原体补偿的强大次级反应的记忆细胞的完全分化。疫苗接种的目的是生成针对病原体特有的记忆淋巴细胞，该病原体可以保护我们一生。 T淋巴细胞，助手和杀手的子集必须合作以保护许多病毒和细菌感染。我们的研究将阐明这种合作，以促进长寿的保护性免疫。 针对传染病的疫苗接种是促进人类健康的最具成本效益的策略。我们的研究旨在发现疫苗输送后长期保护的条件。