T CELL ACTIVATION AND FUNCTIONAL AVIDITY

T 细胞激活和功能亲和力

• 批准号: 8173191
• 负责人: MARK K SLIFKA
• 金额: $ 4.76万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8173191
• 关键词: Acute; Antigens; Antiviral Agents; Avidity; Biological Assay; CD8B1 gene; Cells; Computer Retrieval of Information on Scientific Projects Database; Data; Dose; Funding; Grant; Institution; Kinetics; Lymphocytic choriomeningitis virus; Measures; Mediating; Mus; Peptide/MHC Complex; Peptides; Phenotype; Production; Publishing; Research; Research Personnel; Resources; Source; Surface; T cell response; T-Cell Receptor; T-Lymphocyte; Transgenic Mice; United States National Institutes of Health; Vaccinia; Virus Diseases; cytokine

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have analyzed antigen-specific T cells directly ex vivo using peptide/MHC-tetramers and functional assays that measure cytolytic activity and cytokine production. Following acute viral infection, we have found that T cell responsiveness (termed functional avidity) to peptide antigen increased significantly in both normal and T cell receptor (TcR) transgenic mice, even though TcR avidity remained virtually unaltered. Little is known about the factors involved with determining the kinetics or degree of functional avidity maturation. In our recent studies, we have published a review describing T cell attributes and how they can be modified by adaptive (i.e., peptide stimulation) vs. innate (i.e., cytokine-mediated stimulation) mechanisms of activation. We have also determined the surface phenotype of T cells with high functional avidity. Prior studies had suggested that CTLA-4+ T cells had lower functional avidity than CTLA-4- T cells. Our data refutes this previous observation as we show that CD8+ T cells from LCMV-infected mice respond equally well against graded doses of specific peptide or graded doses of anti-CD3 stimulation, regardless of their expression of CTLA-4 molecules. This is significant because CTLA-4 is considered the predominant down-regulatory molecule on T cells and we show that this is not the case, at least in terms of antiviral T cell responses against either LCMV or vaccinia.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 我们使用肽/MHC 四聚体和功能测定法直接离体分析了抗原特异性 T 细胞， 测量细胞溶解活性和细胞因子的产生。 急性病毒感染后，我们发现 T 细胞反应性（称为 在正常小鼠和 T 细胞受体 (TcR) 转基因小鼠中，对肽抗原的功能性亲合力 (功能亲合力) 显着增加，即使 TcR 热情几乎没有改变。 对于决定功能亲合力成熟的动力学或程度的因素知之甚少。 在我们最近的研究中，我们发表了一篇综述，描述了 T 细胞属性以及如何通过适应性（即肽刺激）与先天（即细胞因子介导的刺激）激活机制来修改它们。 我们还确定了具有高功能亲和力的 T 细胞的表面表型。 先前的研究表明，CTLA-4+ T 细胞的功能亲和力低于 CTLA-4- T 细胞。 我们的数据反驳了之前的观察结果，因为我们表明，来自 LCMV 感染小鼠的 CD8+ T 细胞对分级剂量的特定肽或分级剂量的抗 CD3 刺激反应同样良好，无论其 CTLA-4 分子的表达如何。 这很重要，因为 CTLA-4 被认为是 T 细胞上的主要下调分子，而我们证明情况并非如此，至少在针对 LCMV 或牛痘的抗病毒 T 细胞反应方面。