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: 9206078
• 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/9206078
• 关键词: Adaptive Immune System; Address; Adjuvant; Antibodies; Antibody-Producing Cells; Antigen-Presenting Cells; Antigens; Autoantibodies; B-Cell Development; B-Lymphocytes; Biological Markers; Biology; Blocking Antibodies; CD4 Positive T Lymphocytes; Cell Communication; Cell Lineage; Cell Maintenance; Cell physiology; Cells; Chromatin; Clinical; Cytokine Gene; DNA Modification Process; Data; Dendritic Cells; Development; Disease; Dissection; Effector Cell; Enzymes; Epigenetic Process; Eragrostis; Event; Future; Generations; Genes; Genetic Transcription; HIV; Health; Helper-Inducer T-Lymphocyte; Histones; Humoral Immunities; Immune response; 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; Methylation; Modeling; Modification; Molecular; Molecular Target; Mouse Strains; Mus; Nucleosomes; Organ; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacology; 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; Translating; Vaccinated; Vaccination; Vaccines; Veterans; Viral; Virus; Virus Diseases; cell fixing; cellular targeting; differentiated B cell; epigenetic regulation; genome-wide; histone modification; imprint; improved; influenza virus vaccine; insight; mouse model; neutralizing antibody; pathogen; permissiveness; 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生成以及对先前遇到的抗原和病原体的记忆的维持。记忆 B 细胞的核心来源，因此对于有效的体液免疫至关重要。蛋白质免疫或病毒感染后，二级淋巴器官内 GC 的形成是由相互作用的专门 CD4+ T 滤泡辅助细胞 (TFH) 驱动的。与抗原特异性 B 细胞一起启动 GC 依赖性中和抗体 (Ab)，其产生对于病毒控制和防御继发感染至关重要，并被用作流感疫苗功效的“生物标志物”。 非常需要了解导致 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 CD4+ T 细胞之间的同源相互作用、GC 反应、为了解决这个问题，我们培育了一系列树突状细胞 (DC) 和 B 细胞上 MHC II 类表达发生改变的小鼠，并检查了对模型蛋白的免疫反应。我们的初步结果表明： 1. TFH 分化是一个多步骤过程，其中传统 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至关重要。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 GC 反应；3. 与目前的模型相比，T 细胞依赖性记忆 B 细胞分化可以在没有强大 GC 的情况下得以保留；反应；4. APC 对 TFH 分化的要求在病毒感染后放宽。这些结果得出了我们的假设。 可以操纵 TFH 发育、生发中心反应和 B 细胞记忆形成的可变空间和时间控制来影响对病毒感染或免疫的反应。在当前的提议中，我们将利用许多小鼠模型来剖析 APC。 -调节TFH分化和流感感染后GC反应的T细胞相互作用首先，我们将定义调节甲型流感的清除和保护的MHCII依赖性同源相互作用。MHCII表达有限的小鼠将抵抗或抵抗肺炎。我们将确定哪些 APC 处理并呈现由效应 T 细胞和 TFH 识别的个体 T 细胞表位，以及何时 TFH 分化足以驱动 GC 反应和 B 细胞记忆的发展。为了推进这个模型，我们将检查由不同 APC 诱导的 TFH 谱系的全基因组组蛋白修饰，这些数据将产生表观遗传和转录。最后，我们将利用我们的模型来确定通过改进的佐剂或表观遗传修饰进行的药理学操作是否可以增强疫苗接种的生物学作用。流感疫苗接种和感染期间的 TFH 分化和生发中心分化以及 B 细胞记忆反应我们将确定调节体液免疫和保护的细胞和分子靶标，以指导未来的研究，以增强对有问题的病毒的免疫反应。对于退伍军人。