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

Michelle K. Gleason, Todd R. Lenvik, Valarie McCullar, Martin Felices, M. Shea O'Brien, Sarah A. Cooley, Michael R. Verneris, Frank Cichocki, Carol J. Holman, Angela Panoskaltsis-Mortari, Toshiro Niki, Mitsuomi Hirashima, Bruce R. Blazar, Jeffrey S. Miller

Research output: Contribution to journalArticlepeer-review

281 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3064-3072
Number of pages9
Issue number13
StatePublished - Mar 29 2012


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