IMMUNOBIOLOGY OF CLASS IB MOLECULES

IB 类分子的免疫生物学

• 批准号: 6374466
• 负责人: Mark J Soloski
• 金额: $ 32.41万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6374466
• 关键词: MHC class I antigen; T cell receptor; antigen presentation; autoantigens; bacterial antigens; cytotoxic T lymphocyte; flow cytometry; gene expression; genetically modified animals; laboratory mouse; major histocompatibility complex; natural killer cells; polymerase chain reaction; protein engineering; receptor expression; tissue /cell culture

The identification and characterization of MHC linked class Ib loci has proven to be a exciting area of investigation. Studies from our laboratory and others have shown that class Ib molecules can function to present peptide and non-peptide epitopes to T cells. Several class Ib molecules have been implicated in the immune response to intracellular bacterial pathogens and mouse/human counterparts have been identified. Furthermore, class Ib molecules have also been found to serve as ligands for NK cells. This information indicates that this subset of MHC class I molecules have evolved to play key roles in the immune process. We propose to design a new murine model for the analysis of mouse and human class Ib function. We will engineer, characterize and express a single chain Qa-1b class Ib molecule as a transgene in class I deficient mice. This mouse model will allow the definition of the role for Qa-1 in the selection of the T cell repertoire. Also we will be able to examine the range of pathogens for which Qa-1 restricted CD8+ effector cells are evoked. We will investigate the role of Qa-1 as a ligand for inhibitory receptors expressed on NK cells as well as CD8+ T cells. We hypothesize that Qa-1 has unique structural features that allow it to both serve as a ligand for both NK receptors and antigen-specific T cell receptors. Lastly, we propose to study the structure of endogenous self-peptides bound to Qa-1 and the physical/chemical definition of ligand binding to Qa- 1. Such studies will allow us to fully understand the peptide features requisite for interaction with the Qa-1 binding site. These studies will not only lend insight into the role of Qa- 1 in the presentation of self peptides to alloreactive T cells, but also facilitate the identification of bacterial and/or TCR/Ig derived peptides presented by Qa-1 to regulatory CD8+ T cells. Also, novel antigen presentation pathways may be revealed. Collectively such studies will provide the basic principles needed for our long term objective, to utilize this novel family of non-polymorphic class I molecules as targets for vaccine strategies and/or immune modulation.

MHC连锁Ib类位点的鉴定和表征已被证明是一个令人兴奋的研究领域。我们和其他实验室的研究表明，Ib类分子可以向T细胞呈递肽和非肽表位。一些Ib类分子与细胞内细菌病原体的免疫反应有关，并且已经确定了小鼠/人类的对应分子。此外，Ib类分子也被发现作为NK细胞的配体。这一信息表明MHC I类分子的这一子集已经进化到在免疫过程中发挥关键作用。我们建议设计一种新的小鼠模型来分析小鼠和人类的Ib类功能。我们将在I类缺陷小鼠中设计，表征和表达单链Qa-1b类Ib分子作为转基因。该小鼠模型将允许定义Qa-1在T细胞库选择中的作用。此外，我们将能够检查的病原体范围，其中Qa-1限制性CD8+效应细胞被诱发。我们将研究Qa-1作为NK细胞和CD8+ T细胞上表达的抑制性受体的配体的作用。我们假设Qa-1具有独特的结构特征，使其可以作为NK受体和抗原特异性T细胞受体的配体。最后，我们建议研究与Qa-1结合的内源性自肽的结构以及与Qa-1结合的配体的物理/化学定义。这样的研究将使我们能够充分了解与Qa-1结合位点相互作用所需的肽特征。这些研究不仅有助于深入了解Qa-1在向同种异体反应性T细胞呈递自身肽中的作用，而且有助于鉴定由Qa-1呈递的细菌和/或TCR/Ig衍生肽对CD8+ T细胞的调节。此外，新的抗原呈递途径也可能被揭示。总的来说，这些研究将为我们的长期目标提供所需的基本原则，利用这一新的非多态性I类分子家族作为疫苗策略和/或免疫调节的靶点。