TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis

Abstract

T cell immunoglobulin-domain and mucin-domain (TIM) proteins constitute a receptor family that was identified first on kidney and liver cells; recently it was also shown to be expressed on T cells. TIM-1 and -3 receptors denote different subsets of T cells and have distinct regulatory effects on T cell function. Ferritin is a spherical protein complex that is formed by 24 subunits of H- and L-ferritin. Ferritin stores iron atoms intracellularly, but it also circulates. H-ferritin, but not L-ferritin, shows saturable binding to subsets of human T and B cells, and its expression is increased in response to inflammation. We demonstrate that mouse TIM-2 is expressed on all splenic B cells, with increased levels on germinal center B cells. TIM-2 also is expressed in the liver, especially in bile duct epithelial cells, and in renal tubule cells. We further demonstrate that TIM-2 is a receptor for H-ferritin, but not for L-ferritin, and expression of TIM-2 permits the cellular uptake of H-ferritin into endosomes. This is the first identification of a receptor for ferritin and reveals a new role for TIM-2.

Serum ferritin regulates blood vessel formation: A role beyond iron storage

“…H-ferritin chains are transcriptionally activated through cytokines such as TNF-␣ (10). The observation that serum ferritin can bind to TIM-2 receptors on mouse lymphocytes suggests that it might be a signal for inflammation (11). The finding by Coffman et al (4) that serum ferritin may regulate vascular remodeling and angiogenesis adds further support to that view.…”

Identification of iron-loaded ferritin as an essential mitogen for cell proliferation and postembryonic development in Drosophila

“…For example, serum ferritin regulates vascular remodeling and angiogenesis, suggesting a role for serum ferritin in cell proliferation [23]. Recently, two ferritin receptors, Tim-2, which binds ferritin heavy chain [24,25], and Scara5, which binds ferritin light chain [26], have been identified. The mammalian ferritin receptors bind serum ferritin, stimulate its endocytosis from the cell surface with consequent iron delivery, and thus promote cell proliferation and organogenesis [23].…”

Human TIM-1 Associates with the TCR Complex and Up-Regulates T Cell Activation Signals

“…As TIM-2 has no homolog in the human genome, we thus considered that the regulation and perhaps function of TIM-1 may differ in rodents and primates. Finally, it is clear that the TIM-family is promiscuous in its use of natural ligands, which include a semaphorin (TIM-2 ligand), ferritin-H (TIM-2 ligand), a galectin (TIM-3 ligand), and another TIM protein called TIM-4 (TIM-1 ligand) (12,(22)(23)(24). We have been unable to convincingly demonstrate interaction of TIM-4 with TIM-1 by physical measures (e.g., surface plasmon resonance, FACS) and only weak interaction by ELISA and have not been able to demonstrate any TIM-4-mediated signaling events through binding TIM-1 (data not shown).…”