Structure/biology of short-lived MHC II-ligand complexes

在上一个授予周期中，我们表征了抗原肽与MHC II类分子结合的动力学中间体。这些中间络合物的特点是亲和力低，结合和解离速度快；它们代表多肽受体形式，在转化为稳定的络合物之前需要发生构象变化。中间复合体可以被流感HA306-318多肽的变体(改变为P1结合残基)和P1口袋中突变的HLA-DR1分子模拟。在下一个周期中，我们建议研究这些短寿命中间复合体的生物学，以解决三个目标：1.体外T细胞对短寿命复合体的反应，预计是无能诱导。2.确定负责无能诱导3a的APC。比较DO-/-、DM-/-和WT胸腺基质细胞3b的肽谱。建立表达DR1突变体(DRbG86Y)的小鼠，该突变体参与短暂的复合体，并研究胸腺细胞的选择。

During the last grant cycle, we have characterized a kinetic intermediate in the binding of antigenic peptides to MHC class II molecules. These intermediate complexes are characterized by low affinity and fast association and disassociation rates; they represent peptide-receptive forms, and require a conformational change to occur before converting to stable complexes. The intermediate complexes can be mimicked by variant of flu HA 306-318 peptide (changes to P1-binding residues) and by an HLA-DR1 molecule mutated in the P1 pocket. During the next cycle, we propose to study the biology of these short-lived intermediate complexes, addressing three aims: 1. Characterization of in vitro T cell responses to short-lived complexes, expected to be anergy induction. 2. Identify APCs responsible for anergy induction 3a. Compare peptide repertoires of DO-/-, DM-/- and WT thymic stromal cells 3b. Generate mice expressing a DR1 mutant (DRbG86Y) that participates in short-lived complexes and study thymocyte selection.