Immunodominance in CD4 T Cell Responses

描述（由申请人提供）：通常，CD4 T细胞对 复合蛋白抗原限于一个或几个肽表位 这种抗原，尽管事实上有许多潜在的肽， 与MHC分子结合并在宿主中引发免疫应答。的 本申请中的实验试图理解体内元件 这决定了CD4 T细胞特异性的选择范围缩小。 我们目前的数据表明，肽的动力学稳定性：MHC II类 复合物是决定特定肽类 II复合物将在发育中的CD4 T细胞中作为主要特异性出现。 反应我们的实验旨在全面研究 肽：在选择用于CD4 T细胞的肽中的II类稳定性 应答我们将确定动力学稳定性在DM中的作用 APC内的编辑，DM介导的肽缔合和解离， 在体外和体内由树突状细胞介导的引发事件中。我们将 使用分子、生物化学和功能方法的组合， 明确和批判性地解决这个问题。我们将评估来自 独立和不相关的来源抗原，以确定连锁程度 肽的动力学稳定性：MHC复合物，DM编辑和 免疫优势此外，为了扩大我们的研究范围， 相关关系，一个主要的方法，将用于在拟议的 实验是设计选择性调节动力学的肽变体， 可用于抗原呈递研究、生物化学 实验和免疫研究。其中的实验 因此，申请试图证明 肽II类复合物动力学稳定性及其免疫学命运 免疫反应的发展。|

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. |