Deficiency of the T cell regulator Casitas B-cell lymphoma-B aggravates atherosclerosis by inducing CD8+ T cell-mediated macrophage death

Abstract 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...

Full description

Saved in:

Bibliographic Details
Published in:	European heart journal 2019-01, Vol.40 (4), p.372-382
Main Authors:	Seijkens, Tom T P, Poels, Kikkie, Meiler, Svenja, van Tiel, Claudia M, Kusters, Pascal J H, Reiche, Myrthe, Atzler, Dorothee, Winkels, Holger, Tjwa, Marc, Poelman, Hessel, Slütter, Bram, Kuiper, Johan, Gijbels, Marion, Kuivenhoven, Jan Albert, Matic, Ljubica Perisic, Paulsson-Berne, Gabrielle, Hedin, Ulf, Hansson, Göran K, Nicolaes, Gerry A F, Daemen, Mat J A P, Weber, Christian, Gerdes, Norbert, de Winther, Menno P J, Lutgens, Esther
Format:	Article
Language:	eng
Subjects:	Basic Science Medicin och hälsovetenskap
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Abstract 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 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.
ISSN:	0195-668X 1522-9645 1522-9645