title: NK cells activated by Interleukin-4 in cooperation with Interleukin-15 exhibit distinctive characteristics.
abstract: Natural killer (NK) cells are known to be activated by Th1-type cytokines, such as IL-2, -12, or -18, and they secrete a large amount of IFN-γ that accelerates Th1-type responses. However, the roles of NK cells in Th2-type responses have remained unclear. Because IL-4 acts as an initiator of Th2-type responses, we examined the characteristics of NK cells in mice overexpressing IL-4. In this study, we report that IL-4 overexpression induces distinctive characteristics of NK cells (B220(high)/CD11b(low)/IL-18Rα(low)), which are different from mature conventional NK (cNK) cells (B220(low)/CD11b(high)/IL-18Rα(high)). IL-4 overexpression induces proliferation of tissue-resident macrophages, which contributes to NK cell proliferation via production of IL-15. These IL-4-induced NK cells (IL4-NK cells) produce higher levels of IFN-γ, IL-10, and GM-CSF, and exhibit high cytotoxicity compared with cNK cells. Furthermore, incubation of cNK cells with IL-15 and IL-4 alters their phenotype to that similar to IL4-NK cells. Finally, parasitic infection, which typically causes strong Th2-type responses, induces the development of NK cells with characteristics similar to IL4-NK cells. These IL4-NK-like cells do not develop in IL-4Rα KO mice by parasitic infection. Collectively, these results suggest a novel role of IL-4 in immune responses through the induction of the unique NK cells.
authors.affiliation: Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan;
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kiniwa
authors.affiliation: Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan; yenomoto@iam.u-tokyo.ac.jp miyajima@iam.u-tokyo.ac.jp.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Enomoto
authors.affiliation: Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan;
authors.forename: Natsumi
authors.initials: N
authors.lastname: Terazawa
authors.affiliation: Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan;
authors.forename: Ai
authors.initials: A
authors.lastname: Omi
authors.affiliation: Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan;
authors.forename: Naoko
authors.initials: N
authors.lastname: Miyata
authors.affiliation: Department of Tropical Medicine, The Jikei University School of Medicine, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishiwata
authors.affiliation: Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan; yenomoto@iam.u-tokyo.ac.jp miyajima@iam.u-tokyo.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miyajima
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D019409:Interleukin-15 / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000469:parasitology; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009559:Nippostrongylus / Q000276:immunology / Q000472:pathogenicity; D053724:Receptors, Interleukin-18 / Q000235:genetics / Q000276:immunology; D019948:Receptors, Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D017206:Strongylida Infections / Q000235:genetics / Q000276:immunology* / Q000469:parasitology
chemical_list: D039481:CD11b Antigen; C556062:IL10 protein, mouse; D019409:Interleukin-15; D053724:Receptors, Interleukin-18; D019948:Receptors, Interleukin-4; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017493:Leukocyte Common Antigens
keywords: IL-15; IL-4; macrophage; natural killer cell