BCR Modulation of MHC Class II Structure and Function

描述（由申请方提供）：抗原之间的同源相互作用 呈递细胞（APC）和CD 4 + T细胞通过T细胞受体介导 识别存在于表面上的抗原肽-II类复合物， 装甲运兵车B细胞不同于其他II类限制性APC，如树突状细胞， 细胞和巨噬细胞，因为它们表达一种克隆限制性的 抗原特异性受体（即，B细胞受体（BCR）），通过该受体， 加工和呈递同源抗原。然而，B细胞也可以处理和 通过液相（F-P）内吞作用呈递非同源抗原，前提是 以足够高浓度存在。使用BCR转基因小鼠 模型，我们分析了这两种途径的抗原处理正常 脾B细胞 有趣的是，与通过F-P内吞作用内化的抗原不同， BCR内化抗原可持续存在于非溶酶体内吞区室中 在B细胞内持续超过24小时。此外，这种持久的BCR内化 抗原可以被加工成肽，支持延长的细胞表面 这些B细胞上的肽-II类复合物的持久性。的目标 这项资助申请的第一个具体目标是更好地了解细胞 BCR内化抗原在细胞内持续存在的生物学基础。 此外，使用肽类II复合物特异性单克隆抗体， (mAb)命名为C4 H3，我们已经确定，肽II类复合物 通过BCR介导的抗原加工形成（称为II型肽-II类 复合物在生物学上不同于通过以下形成的肽II类复合物： F-P抗原加工（称为I型肽-II类复合物）。 具体地，II型与I型肽-II类复合物的C4 H3连接 导致B细胞内不同的细胞信号事件。此外，第二类 而不是I型肽-II类复合物能够介导 结合的C4 H3 mAb的内化。第二个具体目标的目标是 申请资助是为了确定细胞差异的生物学基础 I型与II型肽-II类复合物之间的行为。的目标 本补助金申请的第三个具体目的是确定 I型和II型之间差异的免疫学后果 肽-II类复合物。

DESCRIPTION (provided by applicant): Cognate interactions between antigen presenting cells (APCs) and CD4+ T-cells are mediated by T-cell receptor recognition of antigenic peptide-class II complexes present on the surface of APCs. B-cell are distinct from other class II-restricted APCs such as dendritic cells and macrophages because they express a clonally-restricted antigen-specific receptor (i.e., the B-cell receptor (BCR)) via which they can process and present cognate antigen. However, B-cells can also process and present non-cognate antigen by fluid-phase (F-P) endocytosis provided that it is present as sufficiently high concentration. Using a BCR transgenic mouse model, we have analyzed these two pathways of antigen processing in normal splenic B-cells. Interestingly, unlike antigen internalized via F-P endocytosis, native BCR-internalized antigen can persist in a non-lysosomal endocytic compartment within the B-cell for over 24 hours. Moreover, this persisting BCR-internalized antigen can be processed to peptides, supporting the prolonged cell surface persistence of peptide-class II complexes on these B-cell. The goal of the first specific aim of this grant application is to better understand the cell biology behind the intracellular persistence of BCR-internalized antigen. Furthermore, using a peptide-class II complex-specific monoclonal antibody (mAb) designated C4H3, we have determined that peptide-class II complexes formed via BCR-mediated antigen processing (termed Type II peptide-class II complexes are biologically distinct from peptide-class II complexes formed via F-P antigen processing (termed Type I peptide-class Ii complexes). Specifically, C4H3 ligation of Type II vs. Type I peptide-class II complexes leads to distinct cell signaling events within the B-cell. Moreover, Type II but not Type I peptide-class II complexes are able to mediate the internalization of bound C4H3 mAb. The goal of the second specific aim of this grant application is to determine the cell biological basis for the differences in behavior between Type I vs. Type II peptide-class II complexes. The goal of the third specific aim of this grant application is to determine the immunological consequences of the differences between Type I and Type II peptide-class II complexes.