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 - Slutter, Bram
AU - Kuiper, Johan
AU - Gijbels, Marion
AU - Kuivenhoven, Jan Albert
AU - Matic, Ljubica Perisic
AU - Paulsson-Berne, Gabrielle
AU - Hedin, Ulf
AU - Hansson, Goran 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
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. IFN gamma 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. IFN gamma 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 - Innate and adaptive immune system
KW - Macrophages
KW - T cells
KW - CBL-B
KW - E3 UBIQUITIN LIGASE
KW - GENE
KW - LYMPHOCYTES
U2 - 10.1093/eurheartj/ehy714
DO - 10.1093/eurheartj/ehy714
M3 - Article
SN - 0195-668X
VL - 40
SP - 372
EP - 382
JO - European Heart Journal
JF - European Heart Journal
IS - 4
ER -