Tim-3 is an inducible human natural killer cell receptor that enhances interferon gamma production in response to galectin-9

• Published in: Blood Vol. 119; no. 13; pp. 3064 - 3072
• Main Authors: Gleason, Michelle K., Lenvik, Todd R., McCullar, Valarie, Felices, Martin, O'Brien, M. Shea, Cooley, Sarah A., Verneris, Michael R., Cichocki, Frank, Holman, Carol J., Panoskaltsis-Mortari, Angela, Niki, Toshiro, Hirashima, Mitsuomi, Blazar, Bruce R., Miller, Jeffrey S.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 29.03.2012; Americain Society of Hematology; American Society of Hematology
• Subjects: Adult; Biological and medical sciences; Cells, Cultured; Galectins - genetics; Galectins - metabolism; Galectins - pharmacology; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; HEK293 Cells; Hematologic and hematopoietic diseases; Hematopoietic Stem Cell Transplantation; Hepatitis A Virus Cellular Receptor 2; Humans; Immunobiology; Interferon-gamma - blood; Interferon-gamma - metabolism; Jurkat Cells; Killer Cells, Natural - drug effects; Killer Cells, Natural - metabolism; Leukemia - blood; Leukemia - genetics; Leukemia - immunology; Leukemia - therapy; Medical sciences; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - genetics; Membrane Proteins - metabolism; Membrane Proteins - physiology; Receptors, Natural Killer Cell - genetics; Receptors, Natural Killer Cell - metabolism; Receptors, Natural Killer Cell - physiology; Recombinant Proteins - pharmacology; Natural killer cell; Human; Lectin; Hematology; Galectin 9; Biosynthesis; TIM3 gene; Gamma interferon; Biological receptor
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-06-360321

NK-cell function is regulated by the integration of signals received from activating and inhibitory receptors. Here we show that a novel immune receptor, T-cell Ig and mucin-containing domain-3 (Tim-3), is expressed on resting human NK cells and is up-regulated on activation. The NK92 NK-cell line engineered to overexpress Tim-3 showed a marked increase in IFN-γ production in the presence of soluble rhGal-9 or Raji tumor cells engineered to express Gal-9. The Tim-3+ population of low-dose IL-12/IL-18–activated primary NK cells significantly increased IFN-γ production in response to soluble rhGal-9, Gal-9 presented by cell lines, and primary acute myelogenous leukemia (AML) targets that endogenously express Gal-9. This effect is highly specific as Tim-3 Ab blockade significantly decreased IFN-γ production, and Tim-3 cross-linking induced ERK activation and degradation of IκBα. Exposure to Gal-9–expressing target cells had little effect on CD107a degranulation. Reconstituted NK cells obtained from patients after hematopoietic cell transplantation had diminished expression of Tim-3 compared with paired donors. This observation correlates with the known IFN-γ defect seen early posttransplantation. In conclusion, we show that Tim-3 functions as a human NK-cell coreceptor to enhance IFN-γ production, which has important implications for control of infectious disease and cancer.