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类分子在内体隔室中装有其肽货物。该过程是由Ll样分子HLA-DM（小鼠中的H2-M）催化的。 HLA-DO（小鼠中的H2-O）是MHC编码的LL样分子，在运输到内体隔室期间和运输后与DM相关联。有趣的是，与II类处理途径的所有其他组件不同，DO表达仅限于B细胞和胸腺上皮细胞。现在很明显，确实修改了DM的肽加载活性。 DO的净效应还不太清楚； DO可以根据实验系统促进或抑制II类肽载荷。 DO/H2-O对B细胞的限制表达导致我们假设H2-O主要对通过B细胞受体（BCR）内化的抗原（AGS）发挥影响。我们的初步数据表明，BCR连接会导致H2-O从H2-M快速解离，并且也可以通过内部化BCR进行游离H2-M的戏剧性分室化。在一个隔间内集中了AG表现的关键组成部分清楚地表明了一种机制，仅在BCR与Ag的BCR参与后，H2-O可以显着增强II类表现。这种“焦点”机制对于T依赖性B细胞免疫反应似乎至关重要，特别是对于表达低亲和力BCR的B细胞。这些概念将在本应用程序中直接检查。在AIM 1中，我们将1）确认并扩展我们的研究，研究了BCR绑扎细胞中H2-M解离的研究； 2）确定H2-O和H2-M流量的亚细胞隔室； 3）检查H2-O解离对II类表现的影响。在AIM 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。 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对躯体超数，亲和力成熟和B细胞阳性选择的影响。拟议的研究将阐明在免疫反应期间，在体内H2-O在体内II类抗原处理途径中的作用。这些研究与肿瘤免疫，自身免疫和疫苗发育有关。