Deficiency of the T cell regulator Casitas B-cell lymphoma-B aggravates atherosclerosis by inducing CD8(+) T cell-mediated macrophage death
| Autor: | Norbert Gerdes, Claudia M. van Tiel, Dorothee Atzler, Christian Weber, Myrthe E. Reiche, Hessel Poelman, Svenja Meiler, Marion J.J. Gijbels, Kikkie Poels, Marc Tjwa, Holger Winkels, Ulf Hedin, Gerry A. F. Nicolaes, Jan Albert Kuivenhoven, Pascal J. H. Kusters, Esther Lutgens, Bram Slütter, Gabrielle Paulsson-Berne, Tom Seijkens, Mat J.A.P. Daemen, Göran K. Hansson, Ljubica Perisic Matic, Johan Kuiper, Menno P.J. de Winther |
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| Přispěvatelé: | RS: Carim - B01 Blood proteins & engineering, RS: CARIM - R1.01 - Blood proteins & engineering, Promovendi CD, RS: Carim - B07 The vulnerable plaque: makers and markers, RS: CARIM - R3 - Vascular biology, Pathologie, Moleculaire Genetica, RS: CARIM - R1 - Thrombosis and haemostasis, Biochemie, RS: CARIM - R3.07 - Structure-function analysis of the chemokine interactome for therapeutic targeting and imaging in atherosclerosis, Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), ACS - Atherosclerosis & ischemic syndromes, Medical Biochemistry, Pathology, ACS - Amsterdam Cardiovascular Sciences, AII - Inflammatory diseases, ACS - Heart failure & arrhythmias |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Granzyme B production
Lymphoma B-Cell T cell Innate and adaptive immune system T cells Apoptosis CD8-Positive T-Lymphocytes 030204 cardiovascular system & hematology LYMPHOCYTES Mice 03 medical and health sciences 0302 clinical medicine Immune system Basic Science Vascular Biology medicine Animals Humans Macrophage Cytotoxic T cell Mice Knockout business.industry CBL-B Macrophages 030229 sport sciences T lymphocyte medicine.disease Atherosclerosis Oncogene Protein v-cbl Molecular biology GENE Plaque Atherosclerotic 3. Good health Mice Inbred C57BL Disease Models Animal Phenotype medicine.anatomical_structure Atheroma E3 UBIQUITIN LIGASE Cardiology and Cardiovascular Medicine business CD8 |
| Zdroj: | European Heart Journal, 40(4), 372-382. Oxford University Press European Heart Journal European heart journal, 40(4), 372-382. Oxford University Press European Heart Journal, 40(4), 372-382 |
| ISSN: | 0195-668X |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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