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.
|Han, Jian; Seaman, William E; Di, Xiumin et al. (2011) Iron uptake mediated by binding of H-ferritin to the TIM-2 receptor in mouse cells. PLoS One 6:e23800|
|Li, Li; Fang, Celia J; Ryan, James C et al. (2010) Binding and uptake of H-ferritin are mediated by human transferrin receptor-1. Proc Natl Acad Sci U S A 107:3505-10|
|Todorich, Bozho; Zhang, Xuesheng; Slagle-Webb, Becky et al. (2008) Tim-2 is the receptor for H-ferritin on oligodendrocytes. J Neurochem 107:1495-505|