title: Independent control of natural killer cell responsiveness and homeostasis at steady-state by CD11c+ dendritic cells.
abstract: During infection and inflammation, dendritic cells (DC) provide priming signals for natural killer (NK) cells via mechanisms distinct from their antigen processing and presentation functions. The influence of DC on resting NK cells, i.e. at steady-state, is less well studied. We here demonstrate that as early as 1 day after DC depletion, NK cells in naïve mice downregulated the NKG2D receptor and showed decreased constitutive phosphorylation of AKT and mTOR. Subsequently, apoptotic NK cells appeared in the spleen concomitant with reduced NK cell numbers. At 4 days after the onset of DC depletion, increased NK cell proliferation was seen in the spleen resulting in an accumulation of Ly49 receptor-negative NK cells. In parallel, NK cell responsiveness to ITAM-mediated triggering and cytokine stimulation dropped across maturation stages, suggestive of a functional deficiency independent from the homeostatic effect. A role for IL-15 in maintaining NK cell function was supported by a gene signature analysis of NK cell from DC-depleted mice as well as by in vivo DC transfer experiments. We propose that DC, by means of IL-15 transpresentation, are required to maintain not only homeostasis, but also function, at steady-state. These processes appear to be regulated independently from each other.
authors.affiliation: Center for Hematology and Regenerative Medicine (HERM), Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Thuy Thanh
authors.initials: TT
authors.lastname: Luu
authors.affiliation: Center for Hematology and Regenerative Medicine (HERM), Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sridharan
authors.initials: S
authors.lastname: Ganesan
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Arnika Kathleen
authors.initials: AK
authors.lastname: Wagner
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Dhifaf
authors.initials: D
authors.lastname: Sarhan
authors.affiliation: Center for Hematology and Regenerative Medicine (HERM), Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Stephan
authors.initials: S
authors.lastname: Meinke
authors.affiliation: Institute of Experimental Immunology, University of Bonn, Germany.
authors.forename: Natalio
authors.initials: N
authors.lastname: Garbi
authors.affiliation: German Cancer Research Center DKFZ, Division of Molecular Immunology, Heidelberg, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Hämmerling
authors.affiliation: Center for Hematology and Regenerative Medicine (HERM), Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Evren
authors.initials: E
authors.lastname: Alici
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Klas
authors.initials: K
authors.lastname: Kärre
authors.affiliation: Department of Medicine, Center for Infectious Medicine, F59, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Benedict J
authors.initials: BJ
authors.lastname: Chambers
authors.affiliation: Center for Hematology and Regenerative Medicine (HERM), Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Petter
authors.initials: P
authors.lastname: Höglund
authors.affiliation: Center for Hematology and Regenerative Medicine (HERM), Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Nadir
authors.initials: N
authors.lastname: Kadri
mesh_terms: D000818:Animals; D039521:CD11c Antigen / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D006706:Homeostasis; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D039521:CD11c Antigen; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases