TY - JOUR
T1 - Tim-3 is an inducible human natural killer cell receptor that enhances interferon gamma production in response to galectin-9
AU - Gleason, Michelle K.
AU - Lenvik, Todd R.
AU - McCullar, Valarie
AU - Felices, Martin
AU - O'Brien, M. Shea
AU - Cooley, Sarah A.
AU - Verneris, Michael R.
AU - Cichocki, Frank
AU - Holman, Carol J.
AU - Panoskaltsis-Mortari, Angela
AU - Niki, Toshiro
AU - Hirashima, Mitsuomi
AU - Blazar, Bruce R.
AU - Miller, Jeffrey S.
PY - 2012/3/29
Y1 - 2012/3/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84859192882&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84859192882&partnerID=8YFLogxK
U2 - 10.1182/blood-2011-06-360321
DO - 10.1182/blood-2011-06-360321
M3 - Article
C2 - 22323453
AN - SCOPUS:84859192882
SN - 0006-4971
VL - 119
SP - 3064
EP - 3072
JO - Blood
JF - Blood
IS - 13
ER -
