Role of the Tim-2 Receptor in Immunity and Autoimmunity

Tim-2 受体在免疫和自身免疫中的作用

• 批准号: 6968691
• 负责人: William E Seaman
• 金额: $ 35.06万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6968691
• 关键词: T cell receptor; antibody receptor; autoimmunity; biological signal transduction; ferritin; flow cytometry; immune response; immunity; immunocytochemistry; laboratory mouse; mucins; protein localization; receptor mediated endocytosis

DESCRIPTION (provided by applicant): Our proposed studies regard mouse TIM-2, a member of the TIM receptor family. Other members of this family, TIM-1 and TIM-2, are expressed on Th2 and Thl cells, respectively, and regulate T cell immunity and autoimmunity. By developing new antibodies to TIM-2, we have demonstrated that TIM-2 is, in contrast, expressed on all B cells, with the highest expression on germinal center (GC) B cells. Further, we have used molecular cloning to demonstrate that TIM-2 binds to H-ferritin, produced by macrophages. H- and L-ferritin combine to form ferritin, both within cells and in the circulation. Ferritin serves to oxidize and to store iron, but H-ferritin also binds to previously unidentified receptors on lymphocytes, and ferritin is thereby endocytosed. Our studies provide the first identification of a cell-surface receptor for H-ferritin. Based on our results, we propose that TIM-2 regulates immunity, autoimmunity, and germinal center formation. We further propose that H-ferritin initiates transmembrane signaling through TIM-2 and that TIM-2 facilitates the endocytosis of H-ferritin. Finally, we proposed that immunity and GC formation are dependent on ferritin. To test these hypotheses, we propose four specific aims: Specific Aim 1. Determine the in vivo effect of anti-TIM-2 on immunity and autoimmunity and on germinal center formation Specific Aim 2. Define the transmembrane signals that are generated by TIM-2 and the structural requirements for their generation. Specific Aim 3. Define the subcellular localization and trafficking of TIM-2 in lymphocytes, and their relation to the uptake of H-ferritin. Specific Aim 4. Define the consequences of reduced H-ferritin on immunity and on germinal center formation.

描述(由申请人提供)： 我们建议的研究是关于小鼠TIM-2，TIM受体家族的成员。该家族的其他成员Tim-1和Tim-2分别表达于Th2和Th1细胞上，调节T细胞免疫和自身免疫。通过开发针对TIM-2的新抗体，我们证明了TIM-2在所有B细胞上都有表达，其中生发中心(GC)B细胞上的表达最高。此外，我们还利用分子克隆技术证明了TIM-2与巨噬细胞产生的H-铁蛋白结合。H-和L-铁蛋白结合形成铁蛋白，在细胞内和循环中都是如此。铁蛋白用于氧化和储存铁，但H-铁蛋白也与淋巴细胞上以前未知的受体结合，因此铁蛋白被内吞。我们的研究首次鉴定了H-铁蛋白的细胞表面受体。根据我们的结果，我们认为TIM-2调节免疫、自身免疫和生发中心的形成。我们进一步认为，H-铁蛋白通过TIM-2启动跨膜信号转导，TIM-2促进H-铁蛋白的内吞作用。最后，我们提出免疫和GC的形成依赖于铁蛋白。为了检验这些假设，我们提出了四个具体目标： 特异性目的1.测定抗TIM-2对免疫和自身免疫及生发中心形成的影响 具体目标2.定义TIM-2产生的跨膜信号及其产生的结构要求。 明确TIM-2在淋巴细胞中的亚细胞定位和转运，以及它们与H-铁蛋白摄取的关系。 具体目标4.确定H-铁蛋白降低对免疫和生发中心形成的影响。