Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46.
Natural killer (NK) cells contribute to a variety of innate immune responses to viruses, tumors and allogeneic cells. However, our understanding of NK cell biology is severely limited by the lack of consensus phenotypic definition of these cells across species, by the lack of specific marker to visualize them in situ, and by the lack of a genetic model where NK cells may be selectively ablated. NKp46/CD335 is an Ig-like superfamily cell surface receptor involved in human NK cell activation. In addition to human, we show here that NKp46 is expressed by NK cells in all mouse strains analyzed, as well as in three common monkey species, prompting a unifying phenotypic definition of NK cells across species based on NKp46 cell surface expression. Mouse NKp46 triggers NK cell effector function and allows the detection of NK cells in situ. NKp46 expression parallels cell engagement into NK differentiation programs because it is detected on all NK cells from the immature CD122(+)NK1.1(+)DX5(-) stage and on a minute fraction of NK-like T cells, but not on CD1d-restricted NKT cells. Moreover, human NKp46 promoter drives NK cell selective expression both in vitro and in vivo. Using NKp46 promoter, we generated transgenic mice expressing EGFP and the diphtheria toxin (DT) receptor in NK cells. DT injection in these mice leads to a complete and selective NK cell ablation. This model paves a way for the in vivo characterization and preclinical assessment of NK cell biological function.
Walzer
Thierry
T
Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, 13288 Marseille, France. walzer@ciml.univ-mrs.fr
Bléry
Mathieu
M
Chaix
Julie
J
Fuseri
Nicolas
N
Chasson
Lionel
L
Robbins
Scott H
SH
Jaeger
Sébastien
S
André
Pascale
P
Gauthier
Laurent
L
Daniel
Laurent
L
Chemin
Karine
K
Morel
Yannis
Y
Dalod
Marc
M
Imbert
Jean
J
Pierres
Michel
M
Moretta
Alessandro
A
Romagné
François
F
Vivier
Eric
E
D000818:Animals; D000950:Antigens, Ly; D002454:Cell Differentiation / Q000276:immunology; D004167:Diphtheria Toxin / Q000633:toxicity; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D000882:Haplorhini; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D055627:Natural Cytotoxicity Triggering Receptor 1; D011401:Promoter Regions, Genetic / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*
D000950:Antigens, Ly; D004167:Diphtheria Toxin; D008562:Membrane Glycoproteins; D055627:Natural Cytotoxicity Triggering Receptor 1; C118384:Ncr1 protein, mouse; D011971:Receptors, Immunologic; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins