DENDRITIC AND T CELLS IN ANTI-BACTERIAL lg RESPONSES

树突状细胞和 T 细胞在抗细菌 lg 反应中的作用

基本信息

批准号：
7782763
负责人：
CLIFFORD M SNAPPER
金额：
$ 32.15万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7782763
关键词：
Adoptive Transfer Anti-Bacterial Agents Antibodies Antigens B-Lymphocyte Subsets B-Lymphocytes Bacteria Bacterial Polysaccharides Bacterial Proteins Bacterial Vaccines Binding CD4 Positive T Lymphocytes CD40 Ligand Cell Separation Cell Wall Cells Characteristics Data Dendritic Cells Development Electronics Employee Strikes Enzyme-Linked Immunosorbent Assay Exhibits Foundations Funding Generations Goals Humoral Immunities Image Immune Immunity Immunization Immunoglobulin G Immunoglobulin M Immunoglobulins Immunologic Memory Immunologics In Situ In Vitro Kinetics Knock-in Mouse Light Mediating Memory Microscopic Morbidity - disease rate Nature Physiological Play Pneumonia Polysaccharides Population Problem Solving Production Proteins Receptor Signaling Receptors, Antigen, B-Cell Recruitment Activity Relative (related person)Research Role Serotyping Signal Transduction Specificity Speed Spleen Splenic Tissue Streptococcus pneumoniae T cell response T-Lymphocyte Testing Text Time Transgenic Mice Transgenic Organisms Vaccines Wild Type Mouse adaptive immunity anti-IgG base cell type design enzyme linked immunospot assay extracellular functional status improved in vivo insight mortality novel pathogen pneumococcal surface protein A response spatiotemporal

项目摘要

Streptococcus pneumoniae (Pn)is an extracellular bacterium that is a major cause of global morbidity and mortality. Systemic adaptive immunity to Pn is mediated by antibody, especially IgG specific for the capsular polysaccharide (PS),but also for bacterial proteins. Our long-term goal is to elucidate the cellular mechanismsthat underlie the distinct differences that exist between in vivo anti-PSand anti-protein Ig responses to intact Pn, as a prerequisite to the development of improved vaccines.In contrast to the current dogma, based on using purified PS antigens, that IgG anti-PS responses are T cell-independent, we demonstrated that the IgG anti-PS response to intact Pn is heavily dependent on CD4+ T cells but nevertheless, still exhibits striking differences in kinetics, generation of memory, and the functional roles of dendritic and T cells relative to the co-induced anti-protein response. In light of these data, the central hypothesis that underlies our proposed research is that differential B cell receptor signaling and/or involvement of functionally distinct B cell subsets are the key parametersthat distinguish physiologic anti-PS and anti-protein Ig responses. We will demonstrate that these parameters differentially impact on 1) the temporal compartmentalization of responding B cells within the spleen, and 2) the cellular interactions of the responding B cells with other immune cell types. As a result we will provide a mechanistic basis that will elucidate the observed differences in anti-PS and anti-protein responses. The specific aims are to: 1. Determine the nature and relationships of B cell and dendritic cell subsets, and CD4+ T cells that differentially mediate in vivo anti-PS and anti-protein Ig isotype responses to systemic immunization with intact Pn. We will utilize high speed electronic cell sorting and adoptive transfer of wild-type and genetically altered immune cells combined with ELISPOT and ELISA analyses of antigen-specific Ig isotype production to accomplish thisaim. 2. Determine the mechanism by which B cells, DCs,and CD4+ T cells differentially orchestrate anti-PS and anti-protein responses within a spatiotemporal context. We will utilize B cells from BCR knock-in mice with Ig specificity for Pn-derived PS or protein antigens and T cells from CD4+ TCR transgenic mice with specificity for a Pn-derived protein to accomplish this aim.These cells will be used to conduct in vitro functional studies and confocal microscopic analyses of splenic tissue sections post-immunization. These studies are the first to systematically determine the mechanisms that distinguish anti-PS from anti-protein responses to an intact bacterium and provide novel basic immunologic insights with direct relevanceto the development of anti-bacterial vaccines.

肺炎链球菌 (Pn) 是一种细胞外细菌，是全球发病的主要原因和死亡率。对 Pn 的系统适应性免疫是由抗体介导的，尤其是特异性针对 Pn 的 IgG。荚膜多糖（PS），也可用于细菌蛋白质。我们的长期目标是阐明体内抗PS和抗PS之间存在明显差异的细胞机制抗蛋白 Ig 对完整 Pn 的反应，作为开发改进疫苗的先决条件。与当前的教条相反，基于使用纯化的 PS 抗原，IgG 抗 PS 反应是 T 与细胞无关，我们证明 IgG 抗 PS 对完整 Pn 的反应严重依赖于 CD4+ 尽管如此，T 细胞在动力学、记忆生成和树突状细胞和 T 细胞相对于共同诱导的抗蛋白反应的功能作用。鉴于这些数据，我们提出的研究的核心假设是差异 B 细胞受体功能不同的 B 细胞亚群的信号传导和/或参与是关键参数区分生理性抗 PS 和抗蛋白 Ig 反应。我们将证明这些参数对 1) 响应 B 细胞的时间区划有不同的影响脾脏，2) 响应 B 细胞与其他免疫细胞类型的细胞相互作用。结果我们将提供一个机制基础，阐明所观察到的抗 PS 和抗蛋白差异回应。具体目标是： 1. 确定 B 细胞和树突状细胞亚群以及 CD4+ T 细胞的性质和关系差异介导体内抗 PS 和抗蛋白 Ig 同种型对全身免疫的反应具有完整的 Pn。我们将利用高速电子细胞分选和野生型和过继转移基因改变的免疫细胞结合抗原特异性 Ig 同种型的 ELISPOT 和 ELISA 分析生产来实现这一目标。 2. 确定B细胞、DC和CD4+ T细胞差异协调的机制时空背景下的抗 PS 和抗蛋白反应。我们将利用来自 BCR 的 B 细胞对 Pn 衍生的 PS 或蛋白质抗原以及来自 CD4+ TCR 的 T 细胞具有 Ig 特异性的敲入小鼠对 Pn 衍生蛋白具有特异性的转基因小鼠可实现这一目标。这些细胞将用于对脾组织切片进行体外功能研究和共聚焦显微镜分析免疫后。这些研究首次系统地确定了区分针对完整细菌的抗 PS 和抗蛋白反应，并提供新的基础与抗菌疫苗的开发直接相关的免疫学见解。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pneumococcal Surface Protein A Plays a Major Role in Streptococcus pneumoniae-Induced Immunosuppression.

DOI：
10.4049/jimmunol.1502709
发表时间：
2016-05-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Saumyaa;Pujanauski L;Colino J;Flora M;Torres RM;Tuomanen E;Snapper CM
通讯作者：
Snapper CM

The critical DNA flanking sequences of a CpG oligodeoxynucleotide, but not the 6 base CpG motif, can be replaced with RNA without quantitative or qualitative changes in Toll-like receptor 9-mediated activity.

CpG 寡脱氧核苷酸的关键 DNA 侧翼序列（但不是 6 碱基 CpG 基序）可以用 RNA 替换，而不会导致 Toll 样受体 9 介导的活性发生量或质的变化。

DOI：
10.1016/j.cellimm.2005.01.010
发表时间：
2004
期刊：
Cellular immunology.
影响因子：
0
作者：
Sen,Goutam;Flora,Michael;Chattopadhyay,Gouri;Klinman,DennisM;Lees,Andrew;Mond,JamesJ;Snapper,CliffordM
通讯作者：
Snapper,CliffordM

A novel ICOS-independent, but CD28- and SAP-dependent, pathway of T cell-dependent, polysaccharide-specific humoral immunity in response to intact Streptococcus pneumoniae versus pneumococcal conjugate vaccine.