title: Modulation of dendritic cell immunobiology via inhibition of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase.
abstract: The maturation status of dendritic cells determines whether interacting T cells are activated or if they become tolerant. Previously we could induce T cell tolerance by applying a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor (HMGCRI) atorvastatin, which also modulates MHC class II expression and has therapeutic potential in autoimmune disease. Here, we aimed at elucidating the impact of this therapeutic strategy on T cell differentiation as a consequence of alterations in dendritic cell function. We investigated the effect of HMGCRI during differentiation of peripheral human monocytes and murine bone marrow precursors to immature DC in vitro and assessed their phenotype. To examine the stimulatory and tolerogenic capacity of these modulated immature dendritic cells, we measured proliferation and suppressive function of CD4+ T cells after stimulation with the modulated immature dendritic cells. We found that an HMGCRI, atorvastatin, prevents dendrite formation during the generation of immature dendritic cells. The modulated immature dendritic cells had a diminished capacity to take up and present antigen as well as to induce an immune response. Of note, the consequence was an increased capacity to differentiate naïve T cells towards a suppressor phenotype that is less sensitive to proinflammatory stimuli and can effectively inhibit the proliferation of T effector cells in vitro. Thus, manipulation of antigen-presenting cells by HMGCRI contributes to an attenuated immune response as shown by promotion of T cells with suppressive capacities.
authors.affiliation: Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany; Max Delbrueck Center for Molecular Medicine Berlin-Buch, Berlin, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Leuenberger
authors.affiliation: NeuroCure Clinical Research Center, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Caspar F
authors.initials: CF
authors.lastname: Pfueller
authors.affiliation: Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Luessi
authors.affiliation: Department of Pediatrics I/Neonatology, University Hospital Essen, Essen, Germany.
authors.forename: Ivo
authors.initials: I
authors.lastname: Bendix
authors.affiliation: Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany; Max Delbrueck Center for Molecular Medicine Berlin-Buch, Berlin, Germany.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Paterka
authors.affiliation: Department of Neurology, Heinrich-Heine-University, Duesseldorf, Germany.
authors.forename: Timour
authors.initials: T
authors.lastname: Prozorovski
authors.affiliation: Institute of Pathology, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Treue
authors.affiliation: Max Delbrueck Center for Molecular Medicine Berlin-Buch, Berlin, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Luenstedt
authors.affiliation: Department of Pediatrics I/Neonatology, University Hospital Essen, Essen, Germany.
authors.forename: Josephine
authors.initials: J
authors.lastname: Herz
authors.affiliation: Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany; Max Delbrueck Center for Molecular Medicine Berlin-Buch, Berlin, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Siffrin
authors.affiliation: Institute for Medical Immunology, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Infante-Duarte
authors.affiliation: Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany; Max Delbrueck Center for Molecular Medicine Berlin-Buch, Berlin, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Zipp
authors.affiliation: Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Sonia
authors.initials: S
authors.lastname: Waiczies
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D005434:Flow Cytometry; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010587:Phagocytosis / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D016753:Interleukin-10; D000069059:Atorvastatin; D006903:Hydroxymethylglutaryl CoA Reductases