Costimulatory Signals in CD4+ T Cell Activation

CD4 T 细胞激活中的共刺激信号

基本信息

批准号：
8616709
负责人：
Marc Kevin Jenkins
金额：
$ 38万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8616709
关键词：
Achievement Affinity Antibodies Arthritis Autoantigens Autoimmunity Award Bacterial Infections Binding Biological Assay CD28 Antigens CD28 gene CD4 Positive T Lymphocytes Cells Clonal Expansion Development Disease Family Frequencies Funding Goals Graft Rejection Helper-Inducer T-Lymphocyte Immune Immune response Immunity Immunology In Vitro Individual Interleukin-2 Ligands Major Histocompatibility Complex Malignant Neoplasms Mediating Memory Monitor Mus Nature Normal Range Paper Peptides Population Prevention Production Protein Family Publishing Receptor Signaling Regulatory T-Lymphocyte Reliance Rheumatoid Arthritis Role Second Messenger Systems Signal Pathway Signal Transduction Specificity Stimulus Synapses T-Cell Activation T-Cell Receptor T-Lymphocyte Tail Tumor Immunity Uncertainty Validation anergy base candidate identification design improved in vivo killings prevent receptor second messenger therapy development

项目摘要

This proposal is an extension of R37 AI027998, a MERIT award to Marc Jenkins to study the role of D28 family proteins in the provision of costimulatory signals to CD4+ T cells. Significant progress was made in the first 4 years of funding, resulting in 6 senior author paper and 2 middle author papers by Dr. Jenkins. Two of the senior author papers were published in Immunity, 2 in PNAS and 1 in Nature Immunology. These papers and one about to be submitted describe achievement of may ofthe goals of original Specific Aim 1 including development of a sensitive peptide:major histocompatibility complex II (p:MHCIl) tetramer-based cell enrichment assay to detect naive polyclonal p:MHCII-specific CD4+ T cells, validation ofthis assay as a means to monitor clonal expansion, contraction, and memory cell formation from naive p:MHCII-specific precursors during a physiologically relevant bacterial infection, use ofthis assay to show that the major function of CD28 in vivo is to sustain clonal expansion through a signaling pathway involving NFkB but independent of the 2 suspected motifs in the CD28 cytoplamic tail, and identification of the role of CD28 family protein Inducible Costimulator (ICOS) in the formation of central memory cells and follicular helper cells. Progress was also make in Specific Aim 2 including validation of p:MHCIl tetramer-based cell enrichment as a means to study tolerance within polyclonal self-reactive T cell populations in normal repertoires and identification of candidate self antigens of potential relevance to autoimmunity that develops in mice lacking the inhibitory CD28 family protein CTLA-4. Aims forthe extension period include determination of whether CD28 signaling enhances TCR recruitment to the immune synapse in vivo and identification of MHCII-binding peptides in autoantigens from CTLA-4-deficient mice, production of p:MHCII tetramers containing these peptides, and use of these tetramers to determine if CTLA-4 controls autoimmunity by killing self pMHCII-specific T cells, making them anergic, or converting them into regulatory T cells.

该提案是 R37 AI027998 的延伸，R37 AI027998 是 Marc Jenkins 研究 D28 作用的优异奖家族蛋白向 CD4+ T 细胞提供共刺激信号。方面取得了重大进展前 4 年的资助，詹金斯博士发表了 6 篇高级作者论文和 2 篇中间作者论文。两个资深作者论文发表在Immunity、PNAS 2篇、Nature Immunology 1篇。这些论文即将提交的一份报告描述了最初具体目标 1 的许多目标的实现情况，包括敏感肽的开发：基于主要组织相容性复合物 II (p:MHCIl) 四聚体的细胞富集试验检测初始多克隆 p:MHCII 特异性 CD4+ T 细胞，验证该试验作为是指从初始 p:MHCII 特异性中监测克隆扩张、收缩和记忆细胞形成生理相关细菌感染期间的前体，使用该测定来表明主要 CD28 在体内的功能是通过涉及 NFkB 的信号通路维持克隆扩增，但独立于 CD28 胞质尾部的 2 个可疑基序，并鉴定 CD28 的作用家族蛋白诱导共刺激因子 (ICOS) 在中央记忆细胞和卵泡辅助细胞形成中的作用细胞。具体目标 2 也取得了进展，包括基于 p:MHCIl 四聚体的细胞的验证富集作为研究正常情况下多克隆自身反应性 T 细胞群耐受性的一种手段与发展的自身免疫潜在相关的候选自身抗原的库和鉴定缺乏抑制性 CD28 家族蛋白 CTLA-4 的小鼠。延长期限的目标包括确定 CD28 信号传导是否增强体内 TCR 向免疫突触的募集，以及鉴定 CTLA-4 缺陷小鼠自身抗原中的 MHCII 结合肽，生成 p:MHCII 含有这些肽的四聚体，以及使用这些四聚体来确定 CTLA-4 是否控制通过杀死自身 pMHCII 特异性 T 细胞、使其无反应性或将其转化为调节性 T 细胞来产生自身免疫 T 细胞。