Article

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

Veterans Administration Medical Center, San Francisco, CA 94121, USA.
Journal of Experimental Medicine (Impact Factor: 13.91). 11/2005; 202(7):955-65. DOI: 10.1084/jem.20042433
Source: PubMed

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.

2 Followers
 · 
156 Views
  • Source
    • "The recent identification of several members of the Tim family raises an interesting issue on the function of these molecules. Indeed, Tims appear to play a role in diverse biological processes, including cell adhesion, transmembrane transport and nature ligand for virus [1] [2] [3] [4]. Furthermore, all identified members of Tims are essential in the regulation of Th1 and Th2 immune responses [5] [6] [7] [8] [9] [10] [11] [12]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although T-cell immunoglobulin-and mucin-domain containing molecule 3 (Tim-3) was originally identified as a negatively immunoregulator, the role of Tim-3 in regulating immune response is not fully understand. In this study, we report the finding that intratumor injection of pTim-3, a eukaryotic expression plasmid which expresses murine Tim-3 molecule, potently inhibited tumor growth and results in prolonged survival. These results gain further insight into the function of Tim-3 expressed on nonlymphoid tissues in regulating antitumor immune response. Keywords-antitumor immunity; Tim-3; Ectopic expression
    01/2011; DOI:10.1109/icbbe.2011.5779977
  • Source
    • "TIM2 has been shown to be involved in inducing T-cell activation upon binding to Semaphorin 4A (found on B cells and dendritic cells), thereby exerting its effects on the immune system (Kumanogoh et al., 2002). In vitro transfection experiments by Chen et al. (2005) have shown ferritin being sequestered by TIM2 to endosomes, which may be another potential ligand for this molecule. Watanabe et al. (2007) have shown an unknown ligand in the mouse liver that binds to TIM2 through cell-cell contact on adjacent hepatocytes that is capable of inhibiting the negative effect elicited by TIM2 on liver differentiation genes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: T-cell Immunoglobulin and Mucin domain 2 (TIM2) belongs to the receptor family of cell surface molecules expressed on kidney, liver, and T cells. Previous studies have revealed that TIM2-deficient mice (TIM2(-/-)) are more susceptible to the Th2-mediated immune response in an airway inflammation model. Here, we investigated the phenotypic response of TIM2(-/-) mice to cisplatin-induced kidney toxicity. A lethality study in male BALB/c wild-type (TIM2(+/+)) and TIM2(-/-) mice, administered with 20 mg/kg cisplatin ip, resulted in 80% mortality of TIM2(-/-) mice as compared with 30% mortality in the TIM2(+/+) group by day 5. The TIM2(-/-) mice showed approximately fivefold higher injury as estimated by blood urea nitrogen and serum creatinine at 48 h that was confirmed by significantly increased proximal tubular damage assessed histologically (H & E staining). A significantly higher expression of Th2-associated cytokines, TNF-α, IL-1β, IL-6, and TGFβ, with a significant reduction of Th1-associated cytokines, RANTES and MCP-1, by 72 h was observed in the TIM2(-/-) mice as compared with TIM2(+/+) mice. A higher baseline protein expression of caspase-3 (approximately twofold) coupled with an early onset of p53 protein activation by 48 h resulted in an increased apoptosis by 48-72 h in TIM2(-/-) compared with TIM2(+/+). In conclusion, the increased expression of the proinflammatory and proapoptotic genes, with a higher number of apoptotic cells, and a pronounced increase in injury and mortality of the TIM2-deficient mice collectively suggest a protective role of TIM2 in cisplatin-induced nephrotoxicity.
    Toxicological Sciences 11/2010; 118(1):298-306. DOI:10.1093/toxsci/kfq240 · 4.48 Impact Factor
  • Source
    • "Receptor-mediated endocytosis of other forms of protein-bound iron represents an additional means for specific cell types to take up iron: lipocalin 2-dependent endocytosis of an iron-laden siderophore via the SLC22A17 lipocalin receptor has been proposed to modulate the survival of kidney cells in culture (Devireddy et al., 2005), but the physiological relevance of this iron uptake pathway remains uncertain as lipocalin 2 knockout mice develop normally . Serum ferritin can enter cells via the Scara5 (scavenger receptor class A, member 5) and TIM-2 (T cell immunoglobulin and mucin domain containing 2) ferritin receptors (Li et al., 2009, Chen et al., 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Disruptions in iron homeostasis from both iron deficiency and overload account for some of the most common human diseases. Iron metabolism is balanced by two regulatory systems, one that functions systemically and relies on the hormone hepcidin and the iron exporter ferroportin, and another that predominantly controls cellular iron metabolism through iron-regulatory proteins that bind iron-responsive elements in regulated messenger RNAs. We describe how the two distinct systems function and how they "tango" together in a coordinated manner. We also highlight some of the current questions in mammalian iron metabolism and discuss therapeutic opportunities arising from a better understanding of the underlying biological principles.
    Cell 07/2010; 142(1):24-38. DOI:10.1016/j.cell.2010.06.028 · 33.12 Impact Factor
Show more

Preview (3 Sources)

Download
4 Downloads
Available from