Immunodomance in CD Responses

描述(由申请人提供)：我们在前一个资助时期的结果导致我们提出，CD4T细胞反应中的免疫优势在很大程度上取决于多肽的一种内在属性：II类复合体，这是通过其动力学稳定性来衡量的。这一单一参数可以被合理地和实验地操纵，以促进或消除免疫反应。从机制上讲，我们已经确定，在APC中编辑DM是一个关键事件，它会被II类分子的动力学稳定性所改变：多肽复合体。因此，在启动的APC的细胞表面将以比其他竞争的低稳定性肽大得多的初始密度表达高稳定性复合体。在这个新的应用中，使用我们开发的多肽：MHC II类相互作用的工具和知识，我们将把我们的注意力从抗原处理在确定免疫优势中的作用转移到APC-T细胞相互作用的动态和动力学方面，以建立CD4T细胞反应中的多肽层次结构。我们将严格测试初始表位密度是否是规划免疫优势等级的唯一因素。我们假设，多肽：II类复合体的运动稳定性可能在CD4T细胞启动中发挥额外的作用，与DM的影响无关，并且T细胞层次结构可能随着时间的推移和对蛋白质抗原中不同多肽的持续同时反应而重塑。以下是我们解决这些问题的试验性计划。特定目标1：确定CD4T细胞应答中的免疫优势层级何时以及通过什么机制启动和维持特定目标2.确定同时竞争的CD4T细胞对无关多肽的应答在形成免疫优势中的影响。这将为获得和维持抗原特异库的动力学以及T细胞激活、扩张和收缩的竞争性提供一个新的和重要的观点，这是由T细胞受体参与调节的。从这些研究中获得的洞察力将有助于洞察形成CD4T细胞对病原体反应的特异性的因素，并将对寻求集中或多样化CD4T细胞反应的特异性的疫苗的设计产生重大影响。与公共卫生的相关性：在之前的资助期间，我们发现了一个单一的关键因素，它决定了选择病原体或疫苗中的哪些片段作为免疫反应的重点。在计划的实验中，我们将确定这个单一变量如何将免疫反应集中到e病原体的这些有限区域。这些实验的结果将有助于设计集中或多样化对病原体的免疫反应的疫苗。

DESCRIPTION (provided by applicant): Our results in the preceding funding period lead us to propose that immunodominance in CD4 T cell responses is largely dictated by an intrinsic property of the peptide:class II complex, which is measured by its kinetic stability. This single parameter can be rationally and experimentally manipulated to either promote or eliminate immune responses. Mechanistically, we have determined that DM editing in APC is a key event that is altered by the kinetic stability of class II:peptide complexes. Accordingly high stability complexes will be expressed at the cell surface of the priming APC at much greater initial densities than other, competing low stability peptides. In this renewal application, using the tools and knowledge of peptide:MHC class II interactions that we have developed, we will shift our attention from the role of antigen processing in determining immunodominance to the dynamic and kinetic aspects of APC-T cell interactions in establishing peptide hierarchies in CD4 T cell responses. We will critically test whether the initial epitope density is the sole element that programs immunodominance hierarchies. We hypothesize that the kinetic stability of peptide:class II complexes may play additional roles in CD4 T cell priming, independent of DM effects and that T cell hierarchies may be re-shaped over time and by ongoing simultaneous responses to different peptides within the protein antigen. Below are our experimental plans to address these issues. Specific Aim 1: Determine when and through what mechanisms immunodominance hierarchies in CD4 T cell responses are initiated and maintained Specific Aim 2. Determine the impact of simultaneous, competing CD4 T cell responses to unrelated peptides in shaping immunodominance. These will provide a new and significant view of the kinetics of acquisition and maintenance of the antigen-specific repertoire and competitive nature of T cell activation, expansion and contraction that are regulated by T cell receptor engagement. The insight gained from these clarify the studies will help provide insight into the factors that shape the specificity in CD4 T cell responses to pathogens and will have significant impact in the design of vaccines that seek to either focus or alternatively to diversify the specificity of CD4 T cell responses. Public Health Relevance: In the previous funding period, we discovered a single critical factor that determines what segments in the pathogen or vaccines are selected be the focus of the immune response. In the experiments planned, we will determine how this single variable focuses the immune response towards such limited regions of the e pathogen. The results of these experiments will help in the design of vaccines that focus or diversify the immune response to pathogenic organisms.