T CELL ACTIVATION AND FUNCTIONAL AVIDITY

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们已经使用肽/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产生。 在急性病毒感染后，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和力）均显著增加， 实际上，亲合力保持不变。 关于决定功能性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，我们已经发表了一篇综述，描述了T细胞的属性以及它们如何通过自适应（即，肽刺激）与先天性（即，尼古丁介导的刺激）激活机制。 我们还确定了具有高功能亲合力的T细胞的表面表型。 先前的研究表明，CTLA-4+ T细胞具有比CTLA-4- T细胞更低的功能亲合力。 我们的数据反驳了这一先前的观察，因为我们表明，来自LCMV感染小鼠的CD 8 + T细胞对分级剂量的特定肽或分级剂量的抗CD 3刺激的反应同样良好，而不管它们的CTLA-4分子表达如何。 这是重要的，因为CTLA-4被认为是T细胞上的主要下调分子，我们表明情况并非如此，至少在抗LCMV或牛痘的抗病毒T细胞应答方面。

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.