H2-O Mediated Antigen Focusing Modulates B Cell Immunity

H2-O 介导的抗原聚焦调节 B 细胞免疫

基本信息

批准号：
7558276
负责人：
LISA K. DENZIN
金额：
$ 42.46万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-15 至 2011-01-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): MHC class II molecules are loaded with their peptide cargo in endosomal compartments. This process is catalyzed by the class ll-like molecule, HLA-DM (DM; H2-M in mice). HLA-DO (DO; H2-O in mice), an MHC-encoded, class ll-like molecule, associates with DM both during and after transport to endosomal compartments. Intriguingly, unlike all other components of the class II processing pathway, DO expression is restricted to B cells and thymic epithelial cells. It is now clear that DO modifies the peptide loading activity of DM. Less clear is the net effect of DO; DO can promote or inhibit class II peptide loading depending on the experimental system. The restricted expression of DO/H2-O to B cells has led us to hypothesize that H2-O exerts its affects predominantly on antigens (Ags) internalized via the B cell receptor (BCR). Our preliminary data shows that BCR ligation causes rapid dissociation of H2-O from H2-M and, also a dramatic compartmentalization of free H2-M with the internalized BCR. Focusing the critical components of Ag presentation within one compartment clearly suggests a mechanism by which H2-O substantially enhances class II presentation only after the BCR engagement of the BCR with Ag. Such an "Ag focusing" mechanism would appear to be critical for T-dependent B cell immune responses, particularly for B cells expressing low affinity BCR. These concepts will be directly examined in this application. In aim 1 we will 1) confirm and extend our studies examining H2-O dissociation from H2-M in BCR-ligated cells; 2) identify the subcellular compartments to which H2-O and H2-M traffic; and 3) examine the impact that H2-O dissociation has on class II presentation. In aim 2, we will determine the role H2-O plays in T cell-dependent immune response in vivo. The effect of H2-O expression on T cell-dependent, antigen specific antibody responses and germinal center formation will be examined. We will also study the impact of H2-O on somatic hypermutation, affinity maturation and B cell positive selection. The proposed studies will elucidate the role of H2-O in the class II antigen-processing pathway in vivo, during immune responses. These studies are relevant for tumor immunity, autoimmunity and vaccine development.

描述（由申请人提供）：MHC II 类分子在内体区室中装载有其肽货物。该过程由 II 类分子 HLA-DM（DM；小鼠中的 H2-M）催化。 HLA-DO（DO；小鼠体内的 H2-O）是一种 MHC 编码的 II 类分子，在转运至内体区室期间和之后与 DM 相关。有趣的是，与 II 类加工途径的所有其他成分不同，DO 表达仅限于 B 细胞和胸腺上皮细胞。现在已经清楚，DO 可以改变 DM 的肽负载活性。 DO 的净效应不太清楚； DO 可以促进或抑制 II 类肽加载，具体取决于实验系统。 DO/H2-O 在 B 细胞中的表达受到限制，因此我们推测 H2-O 主要对通过 B 细胞受体 (BCR) 内化的抗原 (Ag) 产生影响。我们的初步数据表明，BCR 连接导致 H2-O 从 H2-M 快速解离，并且还导致游离 H2-M 与内化 BCR 的显着区分开。将 Ag 呈递的关键成分集中在一个隔室内，清楚地表明了一种机制，只有在 BCR 与 Ag 结合后，H2-O 才能显着增强 II 类呈递。这种“Ag聚焦”机制似乎对于T依赖性B细胞免疫反应至关重要，特别是对于表达低亲和力BCR的B细胞。这些概念将在本申请中直接检验。在目标 1 中，我们将 1) 确认并扩展我们的研究，检查 BCR 连接细胞中 H2-O 从 H2-M 的解离； 2) 识别 H2-O 和 H2-M 运输的亚细胞区室； 3) 检查 H2-O 解离对 II 类呈现的影响。在目标 2 中，我们将确定 H2-O 在体内 T 细胞依赖性免疫反应中的作用。将检查 H2-O 表达对 T 细胞依赖性、抗原特异性抗体反应和生发中心形成的影响。我们还将研究 H2-O 对体细胞超突变、亲和力成熟和 B 细胞正选择的影响。拟议的研究将阐明 H2-O 在免疫反应过程中体内 II 类抗原加工途径中的作用。这些研究与肿瘤免疫、自身免疫和疫苗开发相关。