IMMUNOBIOLOGY OF CLASS IB MOLECULES

MHC连锁的Ib类基因座的鉴定和特征已被证明是一个令人兴奋的研究领域。我们实验室和其他实验室的研究表明，Ib类分子可以向T细胞呈递多肽和非肽表位。几个Ib类分子参与了对细胞内细菌病原体的免疫反应，并已鉴定出与鼠/人对应的分子。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类分子的这个子集已经进化成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，用于分析小鼠和人类的Ib类功能。我们将设计、表征和表达单链Qa-1b Ib类分子，作为I类基因缺陷小鼠的转基因。这个小鼠模型将允许定义Qa-1在T细胞谱系选择中的作用。此外，我们还将能够检查Qa-1限制的CD8效应细胞被激发的病原体的范围。我们将研究Qa-1作为NK细胞和CD8T细胞上表达的抑制性受体的配基的作用。我们假设Qa-1具有独特的结构特征，这使得它既可以作为NK受体的配体，也可以作为抗原特异性T细胞受体的配体。最后，我们建议研究与Qa-1结合的内源性自体多肽的结构以及与Qa-1结合的配体的物理/化学定义。这些研究将使我们能够充分了解与Qa-1结合位点相互作用所必需的多肽特征。这些研究不仅有助于深入了解Qa-1在自身多肽呈递给同种异体反应性T细胞中的作用，而且有助于鉴定Qa-1呈递给调节性CD8T细胞的细菌和/或TCR/Ig衍生肽。此外，新的抗原提呈途径也可能被揭示。总而言之，这些研究将为我们的长期目标提供所需的基本原则，利用这种新的非多态I类分子家族作为疫苗策略和/或免疫调节的靶标。

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.