Regulation of altered memory CD8 T cell differentiation by co-infection and prolo

共感染和 prolo 改变记忆 CD8 T 细胞分化的调节

• 批准号: 8508812
• 负责人: E. John Wherry
• 金额: $ 29.37万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8508812
• 关键词: Address; Antigens; Antiviral Agents; Blocking Antibodies; CD8B1 gene; Characteristics; Chronic; Communicable Diseases; Development; Environment; Equilibrium; Functional disorder; Gene Expression; Gene Expression Profile; Generations; Genes; Goals; HIV; Hepatitis B Virus; Hepatitis C virus; Humanities; Immune response; Immunity; Immunologic Memory; Infection; Inflammation; Inflammation Mediators; Inflammatory; Lymphocytic choriomeningitis virus; Malaria; Mediating; Memory; Modeling; Molecular; Mus; Pathway interactions; Pattern; Population; Regulation; Role; Shapes; Signal Transduction; Specificity; Staging; T cell differentiation; T memory cell; T-Cell Development; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Tropical Disease; Tuberculosis; Vaccination; Vaccines; base; exhaustion; improved; in vivo; insight; memory process; neglect; pathogen; receptor; transcription factor; vaccination strategy

The development of optimal T cell memory is the goal for many vaccination strategies for infectious disease. Yet the process of memory T cell differentiation and the factors that influence memory T cell quality remain poorly understood. Recent studies have highlighted a key role for inflammatory signals in regulating memory T cell differentiation with evidence indicating that inflammation can be beneficial for T cell priming, but can also induce terminal differentiation of effector T cells. Inflammation is a key feature of most infections, but it is unclear if the effects of unrelated infections can influence T cells of a different specificity in a setting of co-infection. Co-infection can have a negative effect on immunity to unrelated pathogens, but the immunological mechanisms for this effect are not known. In preliminary studies we have found that two types of chronic infections inhibit optimal generation of CD8 T cell memory to unrelated antigens. This effect was not due to persisting antigen since the specificity of the memory CD8 T cells examined was unrelated to the persisting infections. Thus, we hypothesize that the inflammatory environment of chronic infections can negatively impact the pattern of memory T cell differentiation. In this proposal we will test this hypothesis by examining the impact of the inflammatory environment on different subpopulations of effector and memory CD8 T cells and defining the molecular mechanisms for this effect. We will: 1) Determine which stages of memory CD8 T cell development are impacted by co-infection; 2) Define the pathways that regulate memory differentiation during co-infection; and 3) Define the transcriptional pathways controlling arrested memory T cell differentiation due to chronic co-infection. A better understanding of the impact of chronic co-infections on memory T cell differentiation is needed to help optimize antiviral vaccines. Our goal in this project is to begin to address these questions and investigate how bystander chronic infections shape antiviral memory T cell differentiation.

最佳T细胞记忆的发展是许多传染病疫苗接种策略的目标。然而，记忆T细胞分化的过程和影响记忆T细胞质量的因素仍然知之甚少。最近的研究强调了炎症信号在调节记忆T细胞分化中的关键作用，有证据表明炎症可以有益于T细胞引发，但也可以诱导效应T细胞的终末分化。炎症是大多数感染的一个关键特征，但目前尚不清楚无关感染的影响是否会影响合并感染环境中不同特异性的T细胞。合并感染可能对不相关病原体的免疫力产生负面影响，但这种影响的免疫学机制尚不清楚。在初步研究中，我们发现两种类型的慢性感染抑制了CD 8 T细胞对无关抗原记忆的最佳生成。这种效应不是由于持续抗原，因为检测的记忆性CD 8 T细胞的特异性与持续感染无关。因此，我们假设慢性感染的炎症环境可以对记忆T细胞分化的模式产生负面影响。在本提案中，我们将通过检查炎症环境对效应和记忆CD 8 T细胞的不同亚群的影响并定义这种效应的分子机制来验证这一假设。我们将：1）确定记忆性CD 8 T细胞发育的哪个阶段受到共感染的影响; 2）定义在共感染期间调节记忆性分化的途径;以及3）定义控制由于慢性共感染而停滞的记忆性T细胞分化的转录途径。更好地了解慢性合并感染对 需要记忆T细胞分化来帮助优化抗病毒疫苗。我们在这个项目中的目标是开始解决这些问题，并调查旁观者慢性感染如何形成抗病毒记忆T细胞分化。