Distinct MHCII APC Requirements for T Cell and B Cell Effector Functions

T 细胞和 B 细胞效应器功能的不同 MHCII APC 要求

• 批准号: 8920325
• 负责人: TERRI M. LAUFER
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-10-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8920325
• 关键词: Address; Adjuvant; Antibodies; Antigen-Presenting Cells; Antigens; Autoantibodies; B cell differentiation; B-Cell Development; B-Lymphocytes; Biological Markers; Biology; Blocking Antibodies; CD4 Positive T Lymphocytes; Cell Communication; Cell Lineage; Cell Maintenance; Cells; Chromatin; Clinical; Cytokine Gene; DNA Methylation; Data; Dendritic Cells; Development; Disease; Dissection; Effector Cell; Enzymes; Epigenetic Process; Eragrostis; Event; Future; Generations; Genes; HIV; Health; Helper-Inducer T-Lymphocyte; Histones; Humoral Immunities; Immune response; Immune system; Immunization; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin Somatic Hypermutation; Individual; Infection; Influenza; Influenza A virus; Influenza vaccination; Investigation; Lead; Leukocytes; Location; Lupus; Lymphocytic choriomeningitis virus; Lymphoid; MHC Class II Genes; Mediating; Memory; Memory B-Lymphocyte; Modeling; Modification; Molecular; Molecular Target; Mouse Strains; Mus; Nucleosomes; Organ; Outcome; Pathway interactions; Pharmaceutical Preparations; Post-Translational Protein Processing; Process; Proteins; Reaction; Repression; Rheumatoid Arthritis; Series; Site; Soldier; Source; Structure of germinal center of lymph node; T cell differentiation; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Time; Translating; Vaccinated; Vaccination; Vaccines; Veterans; Viral; Virus; Virus Diseases; base; cell fixing; cellular targeting; epigenetic regulation; genome-wide; histone modification; imprint; improved; influenza virus vaccine; insight; mouse model; neutralizing antibody; pathogen; prevent; public health relevance; response; secondary infection; success; transcription factor

 DESCRIPTION (provided by applicant): The success of the adaptive immune system depends upon the rapid generation of effector cells and the maintenance of memory to the antigens and pathogens previously encountered. The germinal center (GC) is the site of somatic hypermutation of antibodies, antibody class switching to IgG, and a central source of memory B cells and thus is critical for effective humoral immunity. The formation of GCs within secondary lymphoid organs after challenge with protein immunizations or viral infections is driven by specialized CD4+ T follicular helper (TFH) cells that interact with antigen-specific B cells to initiate the GC. GC-dependent neutralizing antibodies (Abs) that develop are critical for viral control and defense against secondary infection and are utilized as "biomarkers" for the efficacy of influenza vaccines. Thus, there is a significant need to understand the pathways that lead to differentiation of TFH, GCs, and memory B cells. The cognate interactions between MHC class II positive antigen presenting cells (APC) and antigen-specific CD4+ T cells required for TFH differentiation, the GC reaction, and memory B cell development in different settings and sites remain poorly described. To address this question, we developed a series of mice with altered expression of MHC class II on dendritic cells (DCs) and B cells and examined the immune response to model protein antigens and viral infection. Our preliminary results show that: 1. TFH differentiation is a multi-step process in which conventional DCs are critical for initial priming events but B cells are necessary for imparting the epigenetic changes that mediate complete effector potential; 2. Altering the timing of secondary B cell-T cell interactions preserves the differentiation of TFH bu inhibits the GC response; 3. In contrast to current models, T cell- dependent memory B cell differentiation can be preserved in the absence of robust GC responses; 4. APC requirements for TFH differentiation are relaxed following viral infection. These results lead to our hypothesis that variable spatial and temporal control of TFH development, the germinal center reaction, and B cell memory formation can be manipulated to impact the response to viral infection or immunization. In the current proposal, we will utilize a number of murine models to dissect the APC-T cell interactions that regulate TFH differentiation and the GC response following influenza infection. First, we will define the MHCII- dependent cognate interactions that regulate clearance and protection from influenza A. Mice with limited expression of MHCII will be vaccinated against or infected with Influenza A. We will determine which APCs process and present individual T cell epitopes recognized by effector T cells and TFH and when TFH differentiation is sufficient to drive GC responses and the development of B cell memory. We hypothesize that DCs initiate TFH differentiation but secondary Ag presentation from B cells is necessary to imprint the lineage. To advance this model, we will examine genome wide histone modifications of the TFH lineage induced by different APCs. These data will generate an epigenetic and transcriptional roadmap of the humoral response and define how individual APCs synergize to fix the functional lineages. Finally, we will utilize our models to determine if pharmacologic manipulation with improved adjuvant or epigenetic modification enhances vaccination. Completion of these Aims will provide significant insight into the biology of TFH differentiation and differentiation of the germinal center and B cell memory responses during influenza vaccination and infection. We will identify cellular and molecular targets that regulate humoral immunity and protection to guide future investigations to enhance the immune response to a virus that is problematic for Veterans.

 描述（由申请人提供）： 适应性免疫系统的成功取决于效应细胞的快速产生和对先前遇到的抗原和病原体的记忆的维持。生发中心（GC）是抗体的体细胞超突变、抗体类别转换为IgG的位点，以及记忆B细胞的中心来源，因此对于有效的体液免疫至关重要。在用蛋白质免疫或病毒感染激发后，次级淋巴器官内GC的形成由特化的CD 4 + T滤泡辅助（TFH）细胞驱动，所述TFH细胞与抗原特异性B细胞相互作用以启动GC。产生的GC依赖性中和抗体（Ab）对于病毒控制和防御继发感染至关重要，并用作流感疫苗功效的“生物标志物”。由此可见，有一 因此，有必要了解导致TFH、GC和记忆B细胞分化的途径。MHC II类阳性抗原呈递细胞（APC）和TFH分化所需的抗原特异性CD 4 + T细胞之间的同源相互作用，GC反应和记忆B细胞发育在不同的设置和网站仍然很少描述。为了解决这个问题，我们开发了一系列小鼠的树突状细胞（DC）和B细胞上的MHC II类分子的表达改变，并检查模型蛋白抗原和病毒感染的免疫应答。我们的初步研究结果表明：1. TFH分化是一个多步骤的过程，其中常规DC对于初始引发事件是关键的，但B细胞对于赋予介导完整效应子潜能的表观遗传变化是必需的; 2.改变次级B细胞-T细胞相互作用的时间保留了TFH的分化，但抑制了GC反应; 3.与目前的模型相反，T细胞依赖性记忆B细胞分化可以在不存在稳健的GC应答的情况下被保留; 4.在病毒感染后，TFH分化的APC要求放宽。这些结果导致我们的假设 TFH发展的可变空间和时间控制、生发中心反应和B细胞记忆形成可被操纵以影响对病毒感染或免疫的应答。在目前的建议中，我们将利用一些小鼠模型来剖析APC-T细胞的相互作用，调节TFH分化和GC响应流感感染后。首先，我们将定义MHCII依赖的同源相互作用，调节甲型流感的清除和保护。MHCII表达有限的小鼠将接种甲型流感疫苗或感染甲型流感。我们将确定哪些APC处理和呈递效应T细胞和TFH识别的单个T细胞表位，以及何时TFH分化足以驱动GC应答和B细胞记忆的发展。我们假设DC启动TFH分化，但来自B细胞的次级Ag呈递对于印记该谱系是必要的。为了推进这一模型，我们将研究不同APC诱导的TFH谱系的全基因组蛋白修饰。这些数据将产生体液应答的表观遗传和转录路线图，并定义单个APC如何协同作用以固定功能谱系。最后，我们将利用我们的模型，以确定是否与改进的佐剂或表观遗传修饰的药理学操作增强疫苗接种。这些目标的完成将提供对TFH分化的生物学和在流感疫苗接种和感染期间生发中心的分化和B细胞记忆应答的重要洞察。我们将确定调节体液免疫和保护的细胞和分子靶点，以指导未来的研究，以增强对退伍军人有问题的病毒的免疫反应。