title: Abrogated transforming growth factor beta receptor II (TGFβRII) signalling in dendritic cells promotes immune reactivity of T cells resulting in enhanced atherosclerosis.
abstract: OBJECTIVE
  The importance of transforming growth factor beta (TGFβ) as an immune regulatory cytokine in atherosclerosis has been established. However, the role of TGFβ signalling in dendritic cells (DCs) and in DC-mediated T cell proliferation and differentiation in atherosclerosis is unknown.
  
  
  RESULTS
  Here, we investigated the effect of disrupted TGFβ signalling in DCs on atherosclerosis by using mice carrying a transgene resulting in functional inactivation of TGFβ receptor II (TGFβRII) signalling in CD11c(+) cells (Apoe(-/-)CD11cDNR). Apoe(-/-)CD11cDNR mice exhibited an over two-fold increase in the plaque area compared with Apoe(-/-) mice. Plaques of Apoe(-/-)CD11cDNR mice showed an increase in CD45(+) leucocyte content, and specifically in CD3(+), CD4(+) and CD8(+) cells, whereas macrophage content was not affected. In lymphoid organs, Apoe(-/-)CD11cDNR mice had equal amounts of CD11c(+) cells, and CD11c(+)CD8(+) and CD11c(+)CD8(-) subsets, but showed a subtle shift in the CD11c(+)CD8(-) population towards the more inflammatory CD11c(+)CD8(-)CD4(-) DC subset. In addition, the number of plasmacytoid-DCs decreased. Maturation markers such as MHCII, CD86 and CD40 on CD11c(hi) cells did not change, but the CD11cDNR DCs produced more TNFα and IL-12. CD11c(+) cells from CD11cDNR mice strongly induced T-cell proliferation and activation, resulting in increased amounts of effector T cells producing high amounts of Th1 (IFN-γ), Th2 (IL-4, IL-10), Th17 (IL-17), and Treg (IL-10) cytokines.
  
  
  CONCLUSIONS
  Here, we show that loss of TGFβRII signalling in CD11c(+) cells induces subtle changes in DC subsets, which provoke uncontrolled T cell activation and maturation. This results in increased atherosclerosis and an inflammatory plaque phenotype during hypercholesterolaemia.
authors.affiliation: Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University (LMU), Pettenkoferstr. 9, 80336 Munich, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Lievens
authors.forename: Kim L
authors.initials: KL
authors.lastname: Habets
authors.forename: Anna-Karin
authors.initials: AK
authors.lastname: Robertson
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Laouar
authors.forename: Holger
authors.initials: H
authors.lastname: Winkels
authors.forename: Timo
authors.initials: T
authors.lastname: Rademakers
authors.forename: Linda
authors.initials: L
authors.lastname: Beckers
authors.forename: Erwin
authors.initials: E
authors.lastname: Wijnands
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Munir
authors.initials: M
authors.lastname: Mosaheb
authors.forename: Hafid
authors.initials: H
authors.lastname: Ait-Oufella
authors.forename: Ziad
authors.initials: Z
authors.lastname: Mallat
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Mats
authors.initials: M
authors.lastname: Rudling
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Binder
authors.forename: Norbert
authors.initials: N
authors.lastname: Gerdes
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.forename: Mat J A P
authors.initials: MJ
authors.lastname: Daemen
authors.forename: Johan
authors.initials: J
authors.lastname: Kuiper
authors.forename: Esther
authors.initials: E
authors.lastname: Lutgens
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000276:immunology*; D018845:CD11 Antigens / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D006937:Hypercholesterolemia / Q000276:immunology; D007111:Immunity, Cellular / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018845:CD11 Antigens; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II