Immunodominance in CD4 T Cell Responses

描述(由申请人提供)：通常，CD4T细胞对 复合蛋白抗原仅限于一个或几个多肽表位 这种抗原，尽管有许多潜在的多肽可以 与MHC分子结合，在宿主体内引发免疫反应。这个 这一应用程序中的实验试图了解体内的元素 这就决定了CD4T细胞的特异性选择范围缩小了。 我们目前的数据表明，多肽：MHC II类的动力学稳定性 复合体是决定一种特定的肽：类 II复合体将成为发育中的CD4T细胞的显性特异性 回应。我们的实验旨在全面检查 多肽：CD4T细胞多肽选择的II类稳定性 回应。我们将确定运动稳定性在糖尿病中所起的作用 在APC内编辑，在DM介导肽的关联和解离中 在体外和由树突状细胞介导的体内启动事件中。我们会 使用分子、生化和功能方法的组合来 最终和批判性地解决这个问题。我们将从以下方面评估多肽 确定连锁程度的独立和不相关的来源抗原 多肽的动力学稳定性：MHC络合物、DM编辑和 免疫优势。此外，为了将我们的研究扩展到更远的地方 相关关系，这是拟议中将使用的主要方法 实验是设计选择性调节动力学的多肽变体 稳定性可用于抗原呈递研究、生物化学 在实验和免疫研究中。这里面的实验 因此，应用程序试图证明 多肽II类复合体的动力学稳定性及其免疫学归宿 在发育中的免疫反应中。|

DESCRIPTION (provided by the applicant): Typically, the CD4 T cell response to complex protein antigens is limited to one or a few peptide epitopes within that antigen, despite the fact that there are many potential peptides that can bind to the MHC molecules and elicit an immune response in the host. The experiments within this application seek to understand the elements in vivo that dictate this narrowed selection of specificity in CD4 T cells. Our current data suggest that the kinetic stability of peptide:MHC class II complexes is a major element that determines whether a particular peptide:class II complex will emerge as the dominant specificity in the developing CD4 T cell response. Our experiments are designed to comprehensively examine the impact of peptide:class II stability in the selection of peptides for CD4 T cell responses. We will determine the role that kinetic stability plays in DM editing within APC, in DM-mediated peptide association and dissociation in vitro and in the priming events in vivo mediated by dendritic cells. We will use a combination of molecular, biochemical and functional approaches to definitively and critically address this issue. We will evaluate peptides from independent and unrelated source antigens to determine degree of linkage between kinetic stability of peptide:MHC complexes, DM editing and immunodominance. Additionally, in order to extend our studies beyond correlative relationships, a major approach that will be used in the proposed experiments is to design peptide variants of selectively modulated kinetic stability that can be used in antigen presentation studies, biochemistry experiments and in immunization studies. The experiments within this application thus seek to demonstrate a causative relationship between the kinetic stability of peptide class II complexes with their immunological fate in the developing immune response. |