BCR Modulation of MHC Class II Structure and Function

描述(申请人提供)：抗原之间的同源相互作用 提呈细胞(APC)和CD4+T细胞由T细胞受体介导 细胞表面抗原肽-II类复合体的识别 APC。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，因为它们表达克隆限制性的 抗原特异性受体(即B细胞受体(BCR))，通过这种受体 加工和呈递同源抗原。然而，B细胞也可以处理和 通过液体相(F-P)内吞作用呈递非同源抗原 以足够高的浓度存在。使用BCR转基因小鼠 模型中，我们分析了正常情况下抗原处理的这两条途径。 脾B细胞。 有趣的是，与通过F-P内吞作用内化的抗原不同，天然的 Bcr内化抗原可持续存在于非溶酶体内细胞室 在B细胞内超过24小时。此外，这种持久化的BCR内在化 抗原可以被加工成多肽，支持延长细胞表面 这些B细胞上持续存在多肽-II类复合体。的目标是 这项拨款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。 此外，使用多肽II类复合体特异的单抗 (MAb)命名为C4H3，我们已经确定了多肽-II类复合物 通过BCR介导的抗原处理形成(称为II型多肽-II类 复合体在生物学上不同于通过 F-P抗原处理(称为I型多肽-II类复合体)。 具体地说，C4H3连接II型与I型多肽-II类复合体 导致B细胞内不同的细胞信号事件。此外，类型II 但不是I型多肽-II类复合体能够介导 结合的C4H3单抗的内化。这个目标的第二个具体目标是 GRANT的应用是为了确定差异的细胞生物学基础 在I型和II型多肽类复合体之间的行为。的目标是 这项赠款申请的第三个具体目标是确定 I型和II型差异的免疫学后果 多肽II类复合体。

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.