Publication

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

APA

Seijkens, T. T. P., Poels, K., Meiler, S., van Tiel, C. M., Kusters, P. J. H., Reiche, M., ... Lutgens, E. (2019). Deficiency of the T cell regulator Casitas B-cell lymphoma-B aggravates atherosclerosis by inducing CD8(+) T cell-mediated macrophage death. European Heart Journal, 40(4), 372-382. https://doi.org/10.1093/eurheartj/ehy714

Author

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. / 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. 2019 ; Vol. 40, No. 4. pp. 372-382.

Harvard

Seijkens, TTP, Poels, K, Meiler, S, van Tiel, CM, Kusters, PJH, Reiche, M, Atzler, D, Winkels, H, Tjwa, M, Poelman, H, Slutter, B, Kuiper, J, Gijbels, M, Kuivenhoven, JA, Matic, LP, Paulsson-Berne, G, Hedin, U, Hansson, GK, Nicolaes, GAF, Daemen, MJAP, Weber, C, Gerdes, N, de Winther, MPJ & Lutgens, E 2019, 'Deficiency of the T cell regulator Casitas B-cell lymphoma-B aggravates atherosclerosis by inducing CD8(+) T cell-mediated macrophage death' European Heart Journal, vol. 40, no. 4, pp. 372-382. https://doi.org/10.1093/eurheartj/ehy714

Standard

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

In: European Heart Journal, Vol. 40, No. 4, 21.01.2019, p. 372-382.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Seijkens TTP, Poels K, Meiler S, van Tiel CM, Kusters PJH, Reiche M et al. Deficiency of the T cell regulator Casitas B-cell lymphoma-B aggravates atherosclerosis by inducing CD8(+) T cell-mediated macrophage death. European Heart Journal. 2019 Jan 21;40(4):372-382. https://doi.org/10.1093/eurheartj/ehy714


BibTeX

@article{d0c1e7127da946089861b58a99c78fcb,
title = "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 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.",
keywords = "Atherosclerosis, Innate and adaptive immune system, Macrophages, T cells, CBL-B, E3 UBIQUITIN LIGASE, GENE, LYMPHOCYTES",
author = "Seijkens, {Tom T. P.} and Kikkie Poels and Svenja Meiler and {van Tiel}, {Claudia M.} and Kusters, {Pascal J. H.} and Myrthe Reiche and Dorothee Atzler and Holger Winkels and Marc Tjwa and Hessel Poelman and Bram Slutter and Johan Kuiper and Marion Gijbels and Kuivenhoven, {Jan Albert} and Matic, {Ljubica Perisic} and Gabrielle Paulsson-Berne and Ulf Hedin and Hansson, {Goran K.} and Nicolaes, {Gerry A. F.} and Daemen, {Mat J. A. P.} and Christian Weber and Norbert Gerdes and {de Winther}, {Menno P. J.} and Esther Lutgens",
year = "2019",
month = "1",
day = "21",
doi = "10.1093/eurheartj/ehy714",
language = "English",
volume = "40",
pages = "372--382",
journal = "European Heart Journal",
issn = "0195-668X",
publisher = "Oxford University Press",
number = "4",

}

RIS

TY - JOUR

T1 - Deficiency of the T cell regulator Casitas B-cell lymphoma-B aggravates atherosclerosis by inducing CD8(+) T cell-mediated macrophage death

AU - Seijkens, Tom T. P.

AU - Poels, Kikkie

AU - Meiler, Svenja

AU - van Tiel, Claudia M.

AU - Kusters, Pascal J. H.

AU - Reiche, Myrthe

AU - Atzler, Dorothee

AU - Winkels, Holger

AU - Tjwa, Marc

AU - Poelman, Hessel

AU - Slutter, Bram

AU - Kuiper, Johan

AU - Gijbels, Marion

AU - Kuivenhoven, Jan Albert

AU - Matic, Ljubica Perisic

AU - Paulsson-Berne, Gabrielle

AU - Hedin, Ulf

AU - Hansson, Goran K.

AU - Nicolaes, Gerry A. F.

AU - Daemen, Mat J. A. P.

AU - Weber, Christian

AU - Gerdes, Norbert

AU - de Winther, Menno P. J.

AU - Lutgens, Esther

PY - 2019/1/21

Y1 - 2019/1/21

N2 - 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.

AB - 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.

KW - Atherosclerosis

KW - Innate and adaptive immune system

KW - Macrophages

KW - T cells

KW - CBL-B

KW - E3 UBIQUITIN LIGASE

KW - GENE

KW - LYMPHOCYTES

U2 - 10.1093/eurheartj/ehy714

DO - 10.1093/eurheartj/ehy714

M3 - Article

VL - 40

SP - 372

EP - 382

JO - European Heart Journal

JF - European Heart Journal

SN - 0195-668X

IS - 4

ER -

ID: 91017467