title: IL-21-Induced MHC Class II+ NK Cells Promote the Expansion of Human Uncommitted CD4+ Central Memory T Cells in a Macrophage Migration Inhibitory Factor-Dependent Manner.
abstract: NK cells are critical for innate immunity-mediated protection. The main roles of NK cells rely on their cytotoxic functions or depend on the tuning of Th1 adaptive immunity by IFN-γ. However, the precise influence of inflammatory cytokines on NK cell and CD4 T lymphocyte interactions was never investigated. In this study, we provide evidence that IL-21, a cytokine produced during chronic inflammation or infectious diseases, promotes the differentiation of a specific subset of NK cells coexpressing CD86 and HLA-DR and lacking NKp44. More importantly, IL-21-propagated HLA-DR(+) NK cells produce macrophage migration inhibitory factor and provide costimulatory signaling during naive CD4(+) T cell priming inducing the differentiation of uncommitted central memory T cells. Central memory T cells expanded in the presence of HLA-DR(+) NK cells are CXCR3(+)CCR6(-)CCR4(-)CXCR5(-) and produce IL-2, as well as low levels of TNF-α. Costimulation of CD4(+) T cells by HLA-DR(+) NK cells prevents the acquisition of effector memory phenotype induced by IL-2. Moreover, we identified this population of NK HLA-DR(+) macrophage migration inhibitory factor(+) cells in inflammatory human appendix. Collectively, these results demonstrate a novel function for IL-21 in tuning NK and CD4(+) T cell interactions promoting a specific expansion of central memory lymphocytes.
authors.affiliation: INSERM Unit 1098, University of Franche-Comté, 25000 Besançon, France;
authors.forename: Romain
authors.identifier: 0000-0001-8039-7893
authors.initials: R
authors.lastname: Loyon
authors.affiliation: INSERM Unit 1098, University of Franche-Comté, 25000 Besançon, France;
authors.forename: Emilie
authors.initials: E
authors.lastname: Picard
authors.affiliation: Department of Head and Neck Surgery, University Hospital of Besançon, 25000 Besançon, France;
authors.forename: Olivier
authors.identifier: 0000-0003-4146-3565
authors.initials: O
authors.lastname: Mauvais
authors.affiliation: INSERM Unit 1098, University of Franche-Comté, 25000 Besançon, France; Clinical Investigation Center for Biotherapies, 25000 Besançon, France;
authors.forename: Lise
authors.initials: L
authors.lastname: Queiroz
authors.affiliation: INSERM Unit 1098, University of Franche-Comté, 25000 Besançon, France; Etablissement Français du Sang, 25000 Besançon, France;
authors.forename: Virginie
authors.identifier: 0000-0002-2262-0572
authors.initials: V
authors.lastname: Mougey
authors.affiliation: INSERM Unit 1098, University of Franche-Comté, 25000 Besançon, France; INSERM Unit 1007, University of Paris Descartes, 75270 Paris, France;
authors.forename: Jean-René
authors.initials: JR
authors.lastname: Pallandre
authors.affiliation: INSERM Unit 1098, University of Franche-Comté, 25000 Besançon, France;
authors.forename: Jeanne
authors.initials: J
authors.lastname: Galaine
authors.affiliation: INSERM Unit 1098, University of Franche-Comté, 25000 Besançon, France; Etablissement Français du Sang, 25000 Besançon, France;
authors.forename: Patricia
authors.initials: P
authors.lastname: Mercier-Letondal
authors.affiliation: INSERM Unit 1007, University of Paris Descartes, 75270 Paris, France;
authors.forename: Guillaume
authors.initials: G
authors.lastname: Kellerman
authors.affiliation: INSERM Unit 1015, Gustave Roussy Cancer Campus, 94805 Villejuif, France;
authors.forename: Nathalie
authors.identifier: 0000-0003-2506-7853
authors.initials: N
authors.lastname: Chaput
authors.affiliation: INSERM Unit 1098, University of Franche-Comté, 25000 Besançon, France;
authors.forename: John
authors.initials: J
authors.lastname: Wijdenes
authors.affiliation: INSERM Unit 1098, University of Franche-Comté, 25000 Besançon, France; Clinical Investigation Center for Biotherapies, 25000 Besançon, France; Department of Medical Oncology, University Hospital of Besançon, 25000 Besançon, France; and.
authors.forename: Olivier
authors.initials: O
authors.lastname: Adotévi
authors.affiliation: INSERM Unit 1098, University of Franche-Comté, 25000 Besançon, France; Etablissement Français du Sang, 25000 Besançon, France;
authors.forename: Christophe
authors.identifier: 0000-0003-0119-3919
authors.initials: C
authors.lastname: Ferrand
authors.affiliation: Ludwig Center for Cancer Research of the University of Lausanne, Lausanne 1066, Switzerland.
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
authors.affiliation: INSERM Unit 1098, University of Franche-Comté, 25000 Besançon, France;
authors.forename: Yann
authors.initials: Y
authors.lastname: Godet
authors.affiliation: INSERM Unit 1098, University of Franche-Comté, 25000 Besançon, France; Clinical Investigation Center for Biotherapies, 25000 Besançon, France; Etablissement Français du Sang, 25000 Besançon, France; Department of Medical Oncology, University Hospital of Besançon, 25000 Besançon, France; and christophe.borg@efs.sante.fr.
authors.forename: Christophe
authors.initials: C
authors.lastname: Borg
mesh_terms: D051940:B7-2 Antigen / Q000378:metabolism; D002450:Cell Communication; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D007156:Immunologic Memory; D007249:Inflammation / Q000276:immunology*; D007378:Interleukins / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D014069:Tonsillitis / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: D051940:B7-2 Antigen; D016207:Cytokines; D006684:HLA-DR Antigens; D007378:Interleukins; D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human; D000098546:Interleukin-21