Immunodomance in CD Responses

描述（由申请人提供）：我们在之前资助期的结果使我们提出CD4 T细胞反应中的免疫优势在很大程度上取决于肽的内在特性：II类复合物，这是通过其动力学稳定性来测量的。这一单一参数可以通过合理和实验操作来促进或消除免疫反应。从机制上讲，我们已经确定APC中的DM编辑是由II类肽复合物的动力学稳定性改变的关键事件。因此，高稳定性复合物将以比其他低稳定性肽更大的初始密度在启动APC的细胞表面表达。在这个更新应用中，利用我们开发的肽：MHC II类相互作用的工具和知识，我们将把注意力从抗原加工在确定免疫优势中的作用转移到APC-T细胞相互作用在建立CD4 T细胞反应中的肽层次的动态和动力学方面。我们将严格测试初始表位密度是否是编程免疫优势等级的唯一因素。我们假设肽II类复合物的动力学稳定性可能在CD4 T细胞启动中发挥额外的作用，独立于DM效应，并且T细胞等级可能随着时间的推移和对蛋白质抗原内不同肽的持续同步反应而重新塑造。下面是我们解决这些问题的实验计划。特异性目的1：确定CD4 T细胞应答中的免疫优势等级何时以及通过何种机制启动和维持特异性目的2。确定同时，竞争的CD4 T细胞对不相关肽的反应在形成免疫优势中的影响。这将为获取和维持抗原特异性库的动力学以及T细胞活化、扩张和收缩的竞争性质提供新的和重要的观点，这些都是由T细胞受体参与调节的。从这些研究中获得的见解澄清了这些研究将有助于深入了解形成CD4 T细胞对病原体反应特异性的因素，并将对寻求集中或多样化CD4 T细胞反应特异性的疫苗设计产生重大影响。公共卫生相关性：在上一个资助期内，我们发现了一个单一的关键因素，它决定了病原体或疫苗的哪些部分被选择为免疫反应的重点。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在病原体的有限区域。这些实验的结果将有助于设计针对致病生物的免疫反应集中或多样化的疫苗。

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.