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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; Slutter, Bram; Kuiper, Johan; Gijbels, Marion; Kuivenhoven, Jan Albert; Matic, Ljubica Perisic; Paulsson-Berne, Gabrielle; Hedin, Ulf; Hansson, Goran K.; Nicolaes, Gerry A. F.; Daemen, Mat J. A. P.; Weber, Christian; Gerdes, Norbert; de Winther, Menno P. J.; Lutgens, Esther (2019): Deficiency of the T cell regulator Casitas B-cell lymphoma-B aggravates atherosclerosis by inducing CD8(+) T cell-mediated macrophage death. In: European Heart Journal, Vol. 40, No. 4
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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. 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.