TY - JOUR
T1 - Abrogated transforming growth factor beta receptor II (TGFβRII) signalling in dendritic cells promotes immune reactivity of T cells resulting in enhanced atherosclerosis
AU - Lievens, Dirk
AU - Habets, Kim L.
AU - Robertson, Anna Karin
AU - Laouar, Yasmina
AU - Winkels, Holger
AU - Rademakers, Timo
AU - Beckers, Linda
AU - Wijnands, Erwin
AU - Boon, Louis
AU - Mosaheb, Munir
AU - Ait-Oufella, Hafid
AU - Mallat, Ziad
AU - Flavell, Richard A.
AU - Rudling, Mats
AU - Binder, Christoph J.
AU - Gerdes, Norbert
AU - Biessen, Erik A.L.
AU - Weber, Christian
AU - Daemen, Mat J.A.P.
AU - Kuiper, Johan
AU - Lutgens, Esther
N1 - Funding Information:
This work was supported by the Humboldt Foundation (Sofja Kova-levskaja grant to E.L.), the Netherlands Organization for Scientific Research (VIDI grant to E.L.), and the Netherlands Heart Foundation (established investigator grant to E.L. and E.B.). R.A.F. is an Investigator of the Howard Hughes Medical Institute and A.K.R. was a Wenner-Gren fellow.
PY - 2013/12/21
Y1 - 2013/12/21
N2 - AimsThe 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.Methods and resultsHere, 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 CD11chi 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.ConclusionHere, 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.
AB - AimsThe 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.Methods and resultsHere, 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 CD11chi 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.ConclusionHere, 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.
KW - Atherosclerosis
KW - Dendritic cell
KW - Inflammation
KW - TGFβ
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U2 - 10.1093/eurheartj/ehs106
DO - 10.1093/eurheartj/ehs106
M3 - Article
C2 - 22613345
AN - SCOPUS:84891519471
SN - 0195-668X
VL - 34
SP - 3717
EP - 3727
JO - European heart journal
JF - European heart journal
IS - 48
ER -