Role of the Tim-2 Receptor in Immunity and Autoimmunity

描述（由申请人提供）： 我们提出的研究涉及小鼠TIM-2，TIM受体家族的成员。该家族的其他成员TIM-1和TIM-2分别在Th 2和Th 1细胞上表达，并调节T细胞免疫和自身免疫。通过开发针对TIM-2的新抗体，我们已经证明TIM-2相反地在所有B细胞上表达，其中在生发中心（GC）B细胞上表达最高。此外，我们已经使用分子克隆来证明TIM-2与巨噬细胞产生的H-铁蛋白结合。H-和L-铁蛋白在细胞内和循环中结合联合收割机形成铁蛋白。铁蛋白用于氧化和储存铁，但H-铁蛋白也与淋巴细胞上先前未鉴定的受体结合，铁蛋白因此被内吞。我们的研究提供了H-铁蛋白的细胞表面受体的第一个鉴定。基于我们的研究结果，我们提出TIM-2调节免疫、自身免疫和生发中心的形成。我们进一步提出，H-铁蛋白启动跨膜信号通过TIM-2和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。为了验证这些假设，我们提出了四个具体目标： 具体目标1。确定抗TIM-2对免疫和自身免疫以及对生发中心形成的体内作用 具体目标2。定义由TIM-2产生的跨膜信号及其产生的结构要求。 具体目标3。定义TIM-2在淋巴细胞中的亚细胞定位和运输，以及它们与H-铁蛋白摄取的关系。 具体目标4。定义H-铁蛋白减少对免疫力和生发中心形成的影响。

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.