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

Department of Medicine, University of California, San Francisco, San Francisco, California, United States
Journal of Experimental Medicine (Impact Factor: 12.52). 11/2005; 202(7):955-65. DOI: 10.1084/jem.20042433
Source: PubMed


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.

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    • "The coding sequences of the two proteins were separated by an E2Asequence, which results in equimolar expression from the same transcript [42] (see Figure S1). Human embryonic kidney (HEK 293T) cells stably expressing a luciferase-YFP fusion protein [36], were transduced, at a multiplicity of infection of 2, with LV-PGK-SO, or with a control lentivirus, LV-PGK-ST, in which the coding sequence for Oatp1 was replaced with that of Timd2 [43]. Timd2 is a receptor that mediates H-ferritin endocytosis, and like Oatp1, is expressed on the plasma membrane in liver and kidney cells. "
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    • "Additionally, the TIM-2 knockout murine model displays an exacerbated Th-2-driven response in a model of ovalbumin-induced airway inflammation.7 Semaphorin-4A is a recognized TIM-2 ligand,79 yet semaphorin-4A-deficient mice develop exaggerated Th-2 phenotypes, supporting TIM-2 as an inhibitor of Th-2 responses.80 TIM-2 was also identified as a specific heavy chain ferritin (H-ferritin) receptor leading to endocytosis of extracellular H-ferritin in liver81 and brain.82 H-ferritin has been reported to display immunological properties, mainly as a regulator of proliferation and differentiation of immune cells.83 "
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    • "Serum ferritin is elevated not only in conditions of iron overload, but in acute and chronic inflammation and cancer. Extracellular ferritin binds to cell surface receptors on mouse [16] and human [17] cells, and has been reported to exert a pro-inflammatory effect on hepatic stellate cells [18]. "
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