TY - JOUR
T1 - Deficiency of the T cell regulator Casitas B-cell lymphoma-B aggravates atherosclerosis by inducing CD8 + T cell-mediated macrophage death
AU - Seijkens, Tom T.P.
AU - Poels, Kikkie
AU - Meiler, Svenja
AU - Van Tiel, Claudia M.
AU - Kusters, Pascal J.H.
AU - Reiche, Myrthe
AU - Atzler, Dorothee
AU - Winkels, Holger
AU - Tjwa, Marc
AU - Poelman, Hessel
AU - Slütter, Bram
AU - Kuiper, Johan
AU - Gijbels, Marion
AU - Kuivenhoven, Jan Albert
AU - Matic, Ljubica Perisic
AU - Paulsson-Berne, Gabrielle
AU - Hedin, Ulf
AU - Hansson, Göran K.
AU - Nicolaes, Gerry A.F.
AU - Daemen, Mat J.A.P.
AU - Weber, Christian
AU - Gerdes, Norbert
AU - De Winther, Menno P.J.
AU - Lutgens, Esther
N1 - Funding Information:
This work was supported by The Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands, Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences for the GENIUS-II project ‘Generating the best evidence-based pharmaceutical targets for atherosclerosis-II’ (CVON2018-19). This study was also supported by the Netherlands Organization for Scientific Research (NWO) (VICI grant 016.130.676 to E.L.), the EU (H2020-PHC-2015-667673, REPROGRAM to E.L.), the European Research Council (ERC consolidator grant CD40-INN 681492 to E.L.), the German Science Foundation (DFG, CRC1123, project A5), Amsterdam Cardiovascular Sciences (MD/ PhD grant to T.S.), The Netherlands Heart Institute (Young@heart grant to T.S.), and the Dutch Heart Foundation (Dr Dekker Physician-in-specialty-training grant to T.S.).
Publisher Copyright:
© © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology.
PY - 2019/1/21
Y1 - 2019/1/21
N2 - Aims The E3-ligase CBL-B (Casitas B-cell lymphoma-B) is an important negative regulator of T cell activation that is also expressed in macrophages. T cells and macrophages mediate atherosclerosis, but their regulation in this disease remains largely unknown; thus, we studied the function of CBL-B in atherogenesis. Methods and results The expression of CBL-B in human atherosclerotic plaques was lower in advanced lesions compared with initial lesions and correlated inversely with necrotic core area. Twenty weeks old Cblb-/-Apoe-/-mice showed a significant increase in plaque area in the aortic arch, where initial plaques were present. In the aortic root, a site containing advanced plaques, lesion area rose by 40%, accompanied by a dramatic change in plaque phenotype. Plaques contained fewer macrophages due to increased apoptosis, larger necrotic cores, and more CD8 + T cells. Cblb-/-Apoe-/-macrophages exhibited enhanced migration and increased cytokine production and lipid uptake. Casitas B-cell lymphoma-B deficiency increased CD8 + T cell numbers, which were protected against apoptosis and regulatory T cell-mediated suppression. IFNγ 3 and granzyme B production was enhanced in Cblb-/-Apoe-/-CD8 + T cells, which provoked macrophage killing. Depletion of CD8 + T cells in Cblb-/-Apoe-/-bone marrow chimeras rescued the phenotype, indicating that CBL-B controls atherosclerosis mainly through its function in CD8 + T cells. Conclusion Casitas B-cell lymphoma-B expression in human plaques decreases during the progression of atherosclerosis. As an important regulator of immune responses in experimental atherosclerosis, CBL-B hampers macrophage recruitment and activation during initial atherosclerosis and limits CD8 + T cell activation and CD8 + T cell-mediated macrophage death in advanced atherosclerosis, thereby preventing the progression towards high-risk plaques.
AB - Aims The E3-ligase CBL-B (Casitas B-cell lymphoma-B) is an important negative regulator of T cell activation that is also expressed in macrophages. T cells and macrophages mediate atherosclerosis, but their regulation in this disease remains largely unknown; thus, we studied the function of CBL-B in atherogenesis. Methods and results The expression of CBL-B in human atherosclerotic plaques was lower in advanced lesions compared with initial lesions and correlated inversely with necrotic core area. Twenty weeks old Cblb-/-Apoe-/-mice showed a significant increase in plaque area in the aortic arch, where initial plaques were present. In the aortic root, a site containing advanced plaques, lesion area rose by 40%, accompanied by a dramatic change in plaque phenotype. Plaques contained fewer macrophages due to increased apoptosis, larger necrotic cores, and more CD8 + T cells. Cblb-/-Apoe-/-macrophages exhibited enhanced migration and increased cytokine production and lipid uptake. Casitas B-cell lymphoma-B deficiency increased CD8 + T cell numbers, which were protected against apoptosis and regulatory T cell-mediated suppression. IFNγ 3 and granzyme B production was enhanced in Cblb-/-Apoe-/-CD8 + T cells, which provoked macrophage killing. Depletion of CD8 + T cells in Cblb-/-Apoe-/-bone marrow chimeras rescued the phenotype, indicating that CBL-B controls atherosclerosis mainly through its function in CD8 + T cells. Conclusion Casitas B-cell lymphoma-B expression in human plaques decreases during the progression of atherosclerosis. As an important regulator of immune responses in experimental atherosclerosis, CBL-B hampers macrophage recruitment and activation during initial atherosclerosis and limits CD8 + T cell activation and CD8 + T cell-mediated macrophage death in advanced atherosclerosis, thereby preventing the progression towards high-risk plaques.
KW - Atherosclerosis
KW - CBL-B
KW - Innate and adaptive immune system
KW - Macrophages
KW - T cells
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U2 - 10.1093/eurheartj/ehy714
DO - 10.1093/eurheartj/ehy714
M3 - Article
C2 - 30452556
AN - SCOPUS:85060372106
SN - 0195-668X
VL - 40
SP - 372
EP - 382
JO - European Heart Journal
JF - European Heart Journal
IS - 4
ER -