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

Seijkens, T.T.P.; Poels, K.; Meiler, S.; Tiel, C.M. van; Kusters, P.J.H.; Reiche, M.; Atzler, D.; Winkels, H.; Tjwa, M.; Poelman, H.; Slütter, B.; Kuiper, J.; Gijbels, M.; Kuivenhoven, J.A.; Matic, L.P.; Hedin, U.; Paulsson-Berne, G.; Nicolaes, G.A.F.; Hansson, G.K.; Weber, C.; Daemen, M.J.A.P.; Winther, M.P.J. de; Gerdes, N.; Lutgens, E.

doi:doi:10.1093/eurheartj/ehy714

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.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...Show moreThe 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.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. 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.Show less

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