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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

Seijkens, T. T. P., Poels, K., Meiler, S., van Tiel, C. M., Kusters, P. J. H., Reiche, M., Atzler, D., Winkels, H., Tjwa, M., Poelman, H., Slutter, B., Kuiper, J., Gijbels, M., Kuivenhoven, J. A., Matic, L. P., Paulsson-Berne, G., Hedin, U., Hansson, G. K., Nicolaes, G. A. F., Daemen, M. J. A. P., Weber, C., Gerdes, N., de Winther, M. P. J. & Lutgens, E., 21-Jan-2019, In : European Heart Journal. 40, 4, p. 372-382 12 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • Tom T. P. Seijkens
  • Kikkie Poels
  • Svenja Meiler
  • Claudia M. van Tiel
  • Pascal J. H. Kusters
  • Myrthe Reiche
  • Dorothee Atzler
  • Holger Winkels
  • Marc Tjwa
  • Hessel Poelman
  • Bram Slutter
  • Johan Kuiper
  • Marion Gijbels
  • Jan Albert Kuivenhoven
  • Ljubica Perisic Matic
  • Gabrielle Paulsson-Berne
  • Ulf Hedin
  • Goran K. Hansson
  • Gerry A. F. Nicolaes
  • Mat J. A. P. Daemen
  • Christian Weber
  • Norbert Gerdes
  • Menno P. J. de Winther
  • Esther Lutgens

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.

Original languageEnglish
Pages (from-to)372-382
Number of pages12
JournalEuropean Heart Journal
Volume40
Issue number4
Publication statusPublished - 21-Jan-2019

    Keywords

  • Atherosclerosis, Innate and adaptive immune system, Macrophages, T cells, CBL-B, E3 UBIQUITIN LIGASE, GENE, LYMPHOCYTES

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