title: Conditional ablation of NKp46+ cells using a novel Ncr1(greenCre) mouse strain: NK cells are essential for protection against pulmonary B16 metastases.
abstract: To study gene functions specifically in NKp46+ cells we developed novel Cre mice allowing for conditional gene targeting in cells expressing Ncr1 (encoding NKp46). We generated transgenic Ncr1(greenCre) mice carrying an EGFPcre fusion under the control of a proximal Ncr1 promoter that faithfully directed EGFPcre expression to NKp46+ cells from lymphoid and nonlymphoid tissues. This approach allowed for direct detection of Cre-expressing NKp46+ cells via their GFP signature by flow cytometry and histology. Cre was functional as evidenced by the NKp46+ cell-specific expression of RFP in Ncr1(greenCre) Rosa-dtRFP reporter mice. We generated Ncr1(greenCre) Il2rg(fl/fl) mice that lack NKp46+ cells in an otherwise intact hematopoietic environment. Il2rg encodes the common gamma chain (γc ), which is an essential receptor subunit for cytokines (IL-2, -4, -7, -9, -15, and -21) that stimulate lymphocyte development and function. In Ncr1(greenCre) Il2rg(fl/fl) mice, NK cells are severely reduced and the few remaining NKp46+ cells escaping γc deletion failed to express GFP. Using this new NK-cell-deficient model, we demonstrate that the homeostasis of NKp46+ cells from all tissues (including the recently described intraepithelial ILC1 subset) requires Il2rg. Finally, Ncr1(greenCre) Il2rg(fl/fl) mice are unable to reject B16 lung metastases demonstrating the essential role of NKp46+ cells in antimelanoma immune responses.
authors.affiliation: Département d'Immunologie, Unité d'Immunité Innée, Institut Pasteur, Paris, France; Institut Pasteur, INSERM U668, Paris, France; Cellule Pasteur, Sorbonne Paris Cité, Univ. Paris Diderot, Paris, France.
authors.forename: Leila Ben
authors.initials: LB
authors.lastname: Merzoug
authors.forename: Solenne
authors.initials: S
authors.lastname: Marie
authors.forename: Naoko
authors.initials: N
authors.lastname: Satoh-Takayama
authors.forename: Sarah
authors.initials: S
authors.lastname: Lesjean
authors.forename: Marcello
authors.initials: M
authors.lastname: Albanesi
authors.forename: Hervé
authors.initials: H
authors.lastname: Luche
authors.forename: Hans Jörg
authors.initials: HJ
authors.lastname: Fehling
authors.forename: James P
authors.initials: JP
authors.lastname: Di Santo
authors.forename: Christian A J
authors.initials: CA
authors.lastname: Vosshenrich
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D049452:Green Fluorescent Proteins / Q000235:genetics; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology*; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary*; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D000950:Antigens, Ly; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D055627:Natural Cytotoxicity Triggering Receptor 1; C118384:Ncr1 protein, mouse; D049452:Green Fluorescent Proteins
keywords: Innate immunity; NK cells; NKp46+ cells; Transgenic mouse model; Tumor immunology