Role of the Tim-2 Receptor in Immunity and Autoimmunity

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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.