Priming of Human Resting NK Cells by Autologous M1 Macrophages via the Engagement of IL-1β, IFN-β, and IL-15 Pathways.
The cross talk between NK cells and macrophages is emerging as a major line of defense against microbial infections and tumors. This study reveals a complex network of soluble mediators and cell-to-cell interactions allowing human classically activated (M1) macrophages, but not resting (M0) or alternatively activated (M2) macrophages, to prime resting autologous NK cells. In this article, we show that M1 increase NK cell cytotoxicity by IL-23 and IFN-β-dependent upregulation of NKG2D, IL-1β-dependent upregulation of NKp44, and trans-presentation of IL-15. Moreover, both IFN-β-dependent cis-presentation of IL-15 on NK cells and engagement of the 2B4-CD48 pathway are used by M1 to trigger NK cell production of IFN-γ. The disclosure of these synergic cellular mechanisms regulating the M1-NK cell cross talk provides novel insights to better understand the role of innate immune responses in the physiopathology of tumor biology and microbial infections.
Leukocyte Biology Unit, Humanitas Clinical and Research Center, I-20089 Rozzano, Milan, Italy; Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, I-20089 Rozzano, Milan, Italy; Department of Medical Biotechnologies and Translational Medicine, University of Milan, I-20089 Rozzano, Milan, Italy; and.
Irene
I
Mattiola
Leukocyte Biology Unit, Humanitas Clinical and Research Center, I-20089 Rozzano, Milan, Italy;
Matthieu
M
Pesant
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, I-20089 Rozzano, Milan, Italy;
Paolo F
PF
Tentorio
Leukocyte Biology Unit, Humanitas Clinical and Research Center, I-20089 Rozzano, Milan, Italy; Department of Medical Biotechnologies and Translational Medicine, University of Milan, I-20089 Rozzano, Milan, Italy; and.
Martina
M
Molgora
Dipartimento di Medicina Sperimentale and Centro di Eccellenza per le Ricerche Biomediche, Università degli Studi di Genova, I-16132 Genoa, Italy.
Emanuela
E
Marcenaro
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, I-20089 Rozzano, Milan, Italy;
Enrico
E
Lugli
Leukocyte Biology Unit, Humanitas Clinical and Research Center, I-20089 Rozzano, Milan, Italy; Department of Medical Biotechnologies and Translational Medicine, University of Milan, I-20089 Rozzano, Milan, Italy; and massimo.locati@unimi.it domenico.mavilio@humanitas.it.
Massimo
http://orcid.org/0000-0003-3077-590X
M
Locati
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, I-20089 Rozzano, Milan, Italy; Department of Medical Biotechnologies and Translational Medicine, University of Milan, I-20089 Rozzano, Milan, Italy; and massimo.locati@unimi.it domenico.mavilio@humanitas.it.
Domenico
http://orcid.org/0000-0001-6147-0952
D
Mavilio
D015703:Antigens, CD / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D016899:Interferon-beta / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D019409:Interleukin-15 / Q000276:immunology*; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000276:immunology*; D053760:Interleukin-23 Subunit p19; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis; D055629:Natural Cytotoxicity Triggering Receptor 2 / Q000096:biosynthesis; D011971:Receptors, Immunologic / Q000378:metabolism; D000071176:Signaling Lymphocytic Activation Molecule Family
D015703:Antigens, CD; C084093:CD244 protein, human; C569274:IL15 protein, human; C508585:IL1B protein, human; C508840:IL23A protein, human; D019409:Interleukin-15; D053583:Interleukin-1beta; D053760:Interleukin-23 Subunit p19; C527085:KLRK1 protein, human; C112837:NCR2 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055629:Natural Cytotoxicity Triggering Receptor 2; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family; D016899:Interferon-beta; D007371:Interferon-gamma