Tim-3 is an inducible human natural killer cell receptor that enhances interferon gamma production in response to galectin-9.
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.
Adult Division of Hematology, Oncology and Transplantation, University of Minnesota Cancer Center, Minneapolis, MN 55455, USA.
Michelle K
MK
Gleason
Todd R
TR
Lenvik
Valarie
V
McCullar
Martin
M
Felices
M Shea
MS
O'Brien
Sarah A
SA
Cooley
Michael R
MR
Verneris
Frank
F
Cichocki
Carol J
CJ
Holman
Angela
A
Panoskaltsis-Mortari
Toshiro
T
Niki
Mitsuomi
M
Hirashima
Bruce R
BR
Blazar
Jeffrey S
JS
Miller
D000328:Adult; D002478:Cells, Cultured; D037161:Galectins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D057809:HEK293 Cells; D018380:Hematopoietic Stem Cell Transplantation; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007371:Interferon-gamma / Q000097:blood / Q000378:metabolism*; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism*; D007938:Leukemia / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000628:therapy; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D055607:Receptors, Natural Killer Cell / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology
D037161:Galectins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C105032:LGALS9 protein, human; D008565:Membrane Proteins; D055607:Receptors, Natural Killer Cell; D011994:Recombinant Proteins; D007371:Interferon-gamma