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）： 自适应免疫系统的成功取决于效应细胞的快速产生以及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，抗体类切换到IgG的体细胞超数的部位，并且是记忆B细胞的中心来源，因此对于有效的体液免疫组织化学至关重要。与蛋白质免疫抑制或病毒感染挑战后，GC在次级淋巴机构内的形成是由专门的CD4+ T滤泡辅助（TFH）细胞驱动的，该细胞与抗原特异性B细胞相互作用以启动GC。 GC依赖性的中和抗体（ABS）对于针对继发感染的病毒控制和防御至关重要，并用作影响力疫苗的效率的“生物标志物”。那有一个 了解导致TFH，GC和记忆B细胞区分的途径的重要需求。 MHC II类阳性抗原呈递细胞（APC）与TFH分化所需的抗原特异性CD4+ T细胞之间的同源相互作用，在不同的设置和部位中的记忆B细胞发育仍然很差。为了解决这个问题，我们开发了一系列小鼠，其在树突状细胞（DC）和B细胞上的MHC II类表达改变了，并检查了对蛋白质抗原和病毒感染的模型的免疫响应。我们的初步结果表明：1。TFH分化是一个多步骤过程，其中常规DC对于初始启动事件至关重要，但是B细胞对于赋予介导完整效应子电位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TFH BU的分化抑制GC反应。 3。与当前模型相反，在没有强大的GC响应的情况下，可以保留T细胞依赖性记忆B细胞分化。 4。在病毒感染后，APC的TFH分化要求松弛。这些结果导致了我们的假设 可以操纵对TFH发育，生发中心反应以及B细胞记忆形成的可变空间和临时控制，以影响对病毒感染或免疫抑制的反应。在当前的建议中，我们将利用许多鼠模型来剖析影响TFH分化和影响力后的GC反应的APC-T细胞相互作用。首先，我们将定义MHCII依赖性的认知相互作用，这些相互作用会调节MHCII表达有限或感染流感A。我们假设DC启动TFH分化，但是B细胞的次级AG表现对于烙印谱系是必要的。为了推进这一模型，我们将检查不同APC引起的TFH谱系的基因组广泛的组蛋白修饰。这些数据将产生体外响应的表观遗传和转录路线图，并定义单个APC如何合成以固定功能谱系。最后，我们将利用我们的模型来确定用改善辅助或表观遗传修饰的药理操作是否会增强疫苗接种。这些目的的完成将为TFH疫苗和感染期间的生殖中心和B细胞记忆反应的生物学生物学提供重大见解。我们将确定调节体液免疫学和保护的细胞和分子靶标，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学反应。