Journal
BLOOD
Volume 119, Issue 13, Pages 3064-3072Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-06-360321
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Funding
- National Cancer Institute [P30-CA77598]
- Minnesota Masonic Charities
- National Institutes of Health [P01-CA111412-01, R01 HL55417, R01 CA72669]
- Grants-in-Aid for Scientific Research [23256004, 22590360] Funding Source: KAKEN
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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-gamma 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-gamma 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-gamma production, and Tim-3 cross-linking induced ERK activation and degradation of I kappa B alpha. 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-gamma defect seen early posttransplantation. In conclusion, we show that Tim-3 functions as a human NK-cell coreceptor to enhance IFN-gamma production, which has important implications for control of infectious disease and cancer. (Blood. 2012;119(13):3064-3072)
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