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)： 获得性免疫系统的成功依赖于效应细胞的快速产生和对以前遇到的抗原和病原体的记忆的维持。生发中心(GC)是抗体体细胞高度突变的部位，抗体类型转换为免疫球蛋白G，是记忆B细胞的中心来源，因此对有效的体液免疫至关重要。在蛋白质免疫或病毒感染后，次级淋巴器官内GCs的形成是由特殊的CD4+T滤泡辅助细胞(TFH)细胞驱动的，TFH细胞与抗原特异性B细胞相互作用启动GC。依赖于GC的中和抗体对病毒控制和预防二次感染至关重要，并被用作流感疫苗疗效的“生物标记物”。因此，有一个 有必要了解导致TFH、GC和Memory B细胞分化的途径。MHC-II类阳性抗原提呈细胞(APC)和抗原特异性的CD4+T细胞之间的同源相互作用在不同环境和地点的TFH分化、GC反应和记忆B细胞发育中所需的研究仍然很少。为了解决这个问题，我们开发了一系列在树突状细胞(DC)和B细胞上表达MHC II类的改变的小鼠，并检测了对模型蛋白抗原和病毒感染的免疫反应。我们的初步结果表明：1.TFH的分化是一个多步骤的过程，其中传统的DC对于初始启动事件至关重要，但B细胞对于传递介导完整效应潜力的表观遗传变化是必要的；2.改变次级B细胞-T细胞相互作用的时间可以保留TFH的分化，而Bu抑制GC反应；3.与目前的模型相比，在没有强大的GC反应的情况下，T细胞依赖的记忆B细胞的分化可以被保留；4.病毒感染后APC对TFH分化的要求放松了。这些结果导致了我们的假设 对TFH发生、生发中心反应和B细胞记忆形成的时空可变控制可以被操纵来影响对病毒感染或免疫的反应。在目前的方案中，我们将利用一些小鼠模型来剖析调节TFH分化和流感感染后GC反应的APC-T细胞相互作用。首先，我们将定义依赖于MHCII的同源相互作用，调节对甲型流感的清除和保护。MHCII表达有限的小鼠将被接种或感染甲型流感。我们将确定哪些APC处理并呈现由效应T细胞和TFH识别的单个T细胞表位，以及TFH的分化何时足以驱动GC反应和B细胞记忆的发展。我们假设DC启动了TFH的分化，但B细胞的次级抗原提呈是印记谱系所必需的。为了推进这一模型，我们将检查不同的APC诱导的TFH谱系的全基因组组蛋白修饰。这些数据将产生体液反应的表观遗传和转录路线图，并定义单个APC如何协同修复功能谱系。最后，我们将利用我们的模型来确定改进佐剂或表观遗传修饰的药理操作是否增强了疫苗接种。这些目标的完成将为流感疫苗接种和感染期间TFH的分化和生发中心的分化以及B细胞记忆反应的生物学提供重要的见解。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，以增强对一种对退伍军人有问题的病毒的免疫反应。