MHC Class II subsets in B Lymphocyte Biology

B 淋巴细胞生物学中的 MHC II 类亚群

基本信息

批准号：
7860479
负责人：
James R Drake
金额：
$ 19.75万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-05 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7860479
关键词：
Antigen Presentation Pathway Antigen-Presenting Cells B-Lymphocytes Binding Biochemical CD4 Positive T Lymphocytes Calcium Signaling Carbohydrates Cell Communication Cell Death Cell Fractionation Cell Surface Proteins Cell membrane Cell surface Cells Complex Data Epitopes Exhibits Funding Goals Haplotypes Histocompatibility Antigens Class II Humoral Immunities Immunization Integral Membrane Protein Knowledge Label Link Liquid substance Lymphocyte Biology Lymphoma Major Histocompatibility Complex Mediating Membrane Membrane Lipids Membrane Microdomains Molecular Molecular Structure Monoclonal Antibodies Pathway interactions Patients Peptides Phase Physiologic pulse Positioning Attribute Post-Translational Protein Processing Property Protein Family Proteins Publishing Receptor Signaling Receptors, Antigen, B-Cell Relative (related person)Research Personnel Research Project Grants Rest Role Signal Transduction Surface T-Lymphocyte Testing Up-Regulation Vaccination antigen processing base cancer cell combinatorial dimer improved insight member palmitoylation public health relevance src-Family Kinases tumor

项目摘要

DESCRIPTION (provided by applicant): In addition to mediating activation of CD4 T cells, antigenic peptide-MHC class II complexes transduce signals leading to antigen presenting cell activation. Using well-characterized anti-I-Ak monoclonal antibodies (mAbs) that have been available for over 20 years, we recently established that these mAbs differ in their ability to elicit class II signaling in resting B cells. Specifically, a mAb that binds the 1 chain Ia.2 epitope elicits src family kinase-mediated calcium signaling, while two mAbs that bind the 2 chain Ia.17 epitope do not. In preliminary data presented in this proposal, we further demonstrate that the Ia.2 epitope is not present on all I-Ak molecules as previously thought, but rather marks a subset of cell surface I-Ak class II molecules. Further, in addition to its unique signaling capacity the Ia.2+ subset of I-Ak molecules is highly enriched in lipid rafts, critically involved in initiation of cognate MHC-restricted B cell-T cell interactions, and uniquely associated with a low MW cell surface protein. Based on these published and preliminary results, we put forth the hypothesis that the Ia.2 epitope represents a unique molecular structure generated, or rendered accessible, on a subset of signaling-competent lipid raft-tropic I-Ak class II molecules, which are critically important to key MHC class II functions such as B cell signaling and formation of cognate B cell-T cell interactions. To test this hypothesis, we will accomplish two Specific Aims. First, we will further establish the molecular structure of the Ia.2-bearing lipid raft-tropic signaling-competent subset of I-Ak class II molecules. Second, we will establish the sub-cellular compartment in which Ia.2- bearing I-Ak class II molecules are formed. Completion of these specific aims will reveal the basic molecular mechanism behind the unique signaling properties of Ia.2+ I-Ak class II molecules, establish a molecular mechanism controlling the selective lipid raft partitioning of Ia.2+ I-Ak class II molecules (and other MHC class II haplotypes), and lay the groundwork for the further characterization the role Ia.2+ and other MHC class II subsets in BCR-mediated antigen processing / presentation. PUBLIC HEALTH RELEVANCE: B cell and other antigen presenting cells (APCs) express cell surface proteins called major histocompatibility complex (MHC) class II molecules. Cellular activation signals delivered to these cells through MHC class II molecules are important physiologically for antibody-based immunity (e.g. successful vaccination). Therapeutically, anti-MHC II monoclonal antibodies have been used in lymphoma patients to help eliminate malignant cells by triggering cell death. The increased knowledge of B cell MHC class II signaling gained during this research project will support a greater ability to harness MHC class II signaling for improved immunization and anti-tumor therapy.

描述（由申请人提供）：除了介导CD4 T细胞的激活外，抗原肽-MHC II类复合物转换信号导致抗原呈现细胞激活。使用良好的抗I-AK单克隆抗体（mAb）已有20多年的历史，我们最近确定这些mAB在静止B细胞中引起II类信号传导的能力有所不同。具体而言，一种结合1链IA的mAb。2表位引起SRC家族激酶介导的钙信号传导，而两个结合2链IA.17表位的mAb没有。在本提案中提出的初步数据中，我们进一步证明了IA.2表位并不存在于所有I-AK分子上，而是以前认为的，而是标志着细胞表面I-AK II类分子的子集。此外，除了其独特的信号传导能力外，I-AK分子的2+子集高度富集于脂质筏中，至关重要地参与了同源MHC限制的B细胞-T细胞相互作用的启动，并且与低MW细胞表面蛋白质独特地相关。基于这些已发表和初步的结果，我们提出了IA.2表位代表了在信号能力传导的脂质筏I-AK II类II分子的子集中，代表了产生或易于访问的独特分子结构，对于关键的MHC II类在b型单元格中很重要，例如cysignal belt and-b cellity and consockations cons ackantions cons ackantions cons consipation cons consipation in II至关重要。为了检验这一假设，我们将实现两个具体目标。首先，我们将进一步建立IA.2含有I-AK II类分子的纤维筏 - 向信号能力传导的子集的分子结构。其次，我们将建立IA.2-轴承I-AK II类分子的亚细胞室。这些特定目标的完成将揭示IA.2+ I-AK II类分子独特信号传导特性背后的基本分子机制，建立一个分子机制，该机制控制IA.2+ I-AK类II类分子的选择性脂质筏分配。 BCR介导的抗原加工 /表现。公共卫生相关性：B细胞和其他抗原呈递细胞（APC）表达细胞表面蛋白，称为主要组织相容性复合物（MHC）II类分子。通过MHC II类分子传递到这些细胞的细胞激活信号对于基于抗体的免疫（例如，成功的疫苗接种）至关重要。在治疗上，已在淋巴瘤患者中使用了抗MHC II单克隆抗体，以通过触发细胞死亡来帮助消除恶性细胞。在该研究项目中获得的B细胞MHC II信号传导的知识增加将支持更大的能力利用MHC II类信号传导，以改善免疫和抗肿瘤治疗。