CD27 co-stimulation increases the abundance of regulatory T cells and reduces atherosclerosis in hyperlipidaemic mice

Holger Winkels; Svenja Meiler; Dirk Lievens; David Engel; Charlotte Spitz; Christina Buerger; Linda Beckers; Angelika Dandl; Sigrid Reim; Maiwand Ahmadsei; Helene Hartwig; Lesca M. Holdt; Michael Hristov; Remco T. A. Megens; Martin M. Schmitt; Eric A. Biessen; Jannie Borst; Alexander Faussner; Christian Weber; Esther Lutgens; Norbert Gerdes

doi:10.1093/eurheartj/ehx517

CD27 co-stimulation increases the abundance of regulatory T cells and reduces atherosclerosis in hyperlipidaemic mice

Holger Winkels, Svenja Meiler, Dirk Lievens, David Engel, Charlotte Spitz, Christina Buerger, Linda Beckers, Angelika Dandl, Sigrid Reim, Maiwand Ahmadsei, Helene Hartwig, Lesca M. Holdt, Michael Hristov, Remco T. A. Megens, Martin M. Schmitt, Eric A. Biessen, Jannie Borst, Alexander Faussner, Christian Weber, Esther LutgensNorbert Gerdes^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Aims The co-stimulatory receptor CD27 modulates responses of T cells, B cells, and NK cells. Various T cell subsets participate in atherogenesis. However, the role of CD27 in atherosclerosis remains unexplored.

Methods and results Here we investigated the effect of bone marrow-derived and systemic CD27 deficiency in Apolipoprotein E-deficient (Apoe(-/-)) mice in early and advanced stages of atherosclerosis. Lethally-irradiated Apoe(-/-) mice reconstituted with Cd27(-/-)Apoe(-/-) bone marrow and consuming an atherogenic diet displayed a markedly increased plaque size and lesional inflammation compared to mice receiving Cd27(+/+)Apoe(-/-) bone marrow. Accordingly, chow diet-fed Cd27(-/-)Apoe(-/-) mice showed exacerbated lesion development and increased inflammation at the age of 18 weeks. At a more advanced stage of atherosclerosis (28 weeks), lesion size and phenotype did not differ between the two groups. Systemic and bone marrow-derived CD27 deficiency reduced the abundance of regulatory T cells (Treg) in blood, lymphoid organs, and the aorta. Numbers of other immune cells were not affected while expression of inflammatory cytokine genes (e.g. IL-1 beta and IL-6) was increased in the aorta when haematopoietic CD27 was lacking. In vitro, Tregs of CD27-deficient mice showed similar suppressive capacity compared with their wild-type controls and migrated equally towards CCL19 and CCL21. However, thymic Cd27(-/-) Tregs underwent increased apoptosis and expressed fewer markers of proliferation in vivo. Reconstitution of Cd27(-/-)Apoe(-/-) mice with Cd27(+/+)Apoe(-/-) Tregs reversed the increase in atherosclerosis.

Conclusion We demonstrate that CD27 co-stimulation increases the number of Tregs and limits lesion development and inflammation in experimental atherosclerosis, particularly during early stages of disease. Thus, our study suggests that promotion of CD27 function may mitigate atherosclerosis.

Original language	English
Pages (from-to)	3590-3599
Number of pages	11
Journal	European Heart Journal
Volume	38
Issue number	48
DOIs	https://doi.org/10.1093/eurheartj/ehx517
Publication status	Published - 21 Dec 2017

Keywords

Atherosclerosis
Inflammation
Regulatory T cells
CD27
ACUTE CORONARY SYNDROMES
DENDRITIC CELLS
CD27-CD70 INTERACTIONS
IMMUNE ACTIVATION
KNOCKOUT MICE
CD70
MAINTENANCE
MECHANISMS
PATHWAY
CD40

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10.1093/eurheartj/ehx517

Cite this

Winkels, H., Meiler, S., Lievens, D., Engel, D., Spitz, C., Buerger, C., Beckers, L., Dandl, A., Reim, S., Ahmadsei, M., Hartwig, H., Holdt, L. M., Hristov, M., Megens, R. T. A., Schmitt, M. M., Biessen, E. A., Borst, J., Faussner, A., Weber, C., ... Gerdes, N. (2017). CD27 co-stimulation increases the abundance of regulatory T cells and reduces atherosclerosis in hyperlipidaemic mice. European Heart Journal, 38(48), 3590-3599. https://doi.org/10.1093/eurheartj/ehx517

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title = "CD27 co-stimulation increases the abundance of regulatory T cells and reduces atherosclerosis in hyperlipidaemic mice",

abstract = "Aims The co-stimulatory receptor CD27 modulates responses of T cells, B cells, and NK cells. Various T cell subsets participate in atherogenesis. However, the role of CD27 in atherosclerosis remains unexplored.Methods and results Here we investigated the effect of bone marrow-derived and systemic CD27 deficiency in Apolipoprotein E-deficient (Apoe(-/-)) mice in early and advanced stages of atherosclerosis. Lethally-irradiated Apoe(-/-) mice reconstituted with Cd27(-/-)Apoe(-/-) bone marrow and consuming an atherogenic diet displayed a markedly increased plaque size and lesional inflammation compared to mice receiving Cd27(+/+)Apoe(-/-) bone marrow. Accordingly, chow diet-fed Cd27(-/-)Apoe(-/-) mice showed exacerbated lesion development and increased inflammation at the age of 18 weeks. At a more advanced stage of atherosclerosis (28 weeks), lesion size and phenotype did not differ between the two groups. Systemic and bone marrow-derived CD27 deficiency reduced the abundance of regulatory T cells (Treg) in blood, lymphoid organs, and the aorta. Numbers of other immune cells were not affected while expression of inflammatory cytokine genes (e.g. IL-1 beta and IL-6) was increased in the aorta when haematopoietic CD27 was lacking. In vitro, Tregs of CD27-deficient mice showed similar suppressive capacity compared with their wild-type controls and migrated equally towards CCL19 and CCL21. However, thymic Cd27(-/-) Tregs underwent increased apoptosis and expressed fewer markers of proliferation in vivo. Reconstitution of Cd27(-/-)Apoe(-/-) mice with Cd27(+/+)Apoe(-/-) Tregs reversed the increase in atherosclerosis.Conclusion We demonstrate that CD27 co-stimulation increases the number of Tregs and limits lesion development and inflammation in experimental atherosclerosis, particularly during early stages of disease. Thus, our study suggests that promotion of CD27 function may mitigate atherosclerosis.",

keywords = "Atherosclerosis, Inflammation, Regulatory T cells, CD27, ACUTE CORONARY SYNDROMES, DENDRITIC CELLS, CD27-CD70 INTERACTIONS, IMMUNE ACTIVATION, KNOCKOUT MICE, CD70, MAINTENANCE, MECHANISMS, PATHWAY, CD40",

author = "Holger Winkels and Svenja Meiler and Dirk Lievens and David Engel and Charlotte Spitz and Christina Buerger and Linda Beckers and Angelika Dandl and Sigrid Reim and Maiwand Ahmadsei and Helene Hartwig and Holdt, {Lesca M.} and Michael Hristov and Megens, {Remco T. A.} and Schmitt, {Martin M.} and Biessen, {Eric A.} and Jannie Borst and Alexander Faussner and Christian Weber and Esther Lutgens and Norbert Gerdes",

year = "2017",

month = dec,

day = "21",

doi = "10.1093/eurheartj/ehx517",

language = "English",

volume = "38",

pages = "3590--3599",

journal = "European Heart Journal",

issn = "0195-668X",

publisher = "Oxford University Press",

number = "48",

}

Winkels, H, Meiler, S, Lievens, D, Engel, D, Spitz, C, Buerger, C, Beckers, L, Dandl, A, Reim, S, Ahmadsei, M, Hartwig, H, Holdt, LM, Hristov, M, Megens, RTA, Schmitt, MM, Biessen, EA, Borst, J, Faussner, A, Weber, C, Lutgens, E & Gerdes, N 2017, 'CD27 co-stimulation increases the abundance of regulatory T cells and reduces atherosclerosis in hyperlipidaemic mice', European Heart Journal, vol. 38, no. 48, pp. 3590-3599. https://doi.org/10.1093/eurheartj/ehx517

TY - JOUR

T1 - CD27 co-stimulation increases the abundance of regulatory T cells and reduces atherosclerosis in hyperlipidaemic mice

AU - Winkels, Holger

AU - Meiler, Svenja

AU - Lievens, Dirk

AU - Engel, David

AU - Spitz, Charlotte

AU - Buerger, Christina

AU - Beckers, Linda

AU - Dandl, Angelika

AU - Reim, Sigrid

AU - Ahmadsei, Maiwand

AU - Hartwig, Helene

AU - Holdt, Lesca M.

AU - Hristov, Michael

AU - Megens, Remco T. A.

AU - Schmitt, Martin M.

AU - Biessen, Eric A.

AU - Borst, Jannie

AU - Faussner, Alexander

AU - Weber, Christian

AU - Lutgens, Esther

AU - Gerdes, Norbert

PY - 2017/12/21

Y1 - 2017/12/21

N2 - Aims The co-stimulatory receptor CD27 modulates responses of T cells, B cells, and NK cells. Various T cell subsets participate in atherogenesis. However, the role of CD27 in atherosclerosis remains unexplored.Methods and results Here we investigated the effect of bone marrow-derived and systemic CD27 deficiency in Apolipoprotein E-deficient (Apoe(-/-)) mice in early and advanced stages of atherosclerosis. Lethally-irradiated Apoe(-/-) mice reconstituted with Cd27(-/-)Apoe(-/-) bone marrow and consuming an atherogenic diet displayed a markedly increased plaque size and lesional inflammation compared to mice receiving Cd27(+/+)Apoe(-/-) bone marrow. Accordingly, chow diet-fed Cd27(-/-)Apoe(-/-) mice showed exacerbated lesion development and increased inflammation at the age of 18 weeks. At a more advanced stage of atherosclerosis (28 weeks), lesion size and phenotype did not differ between the two groups. Systemic and bone marrow-derived CD27 deficiency reduced the abundance of regulatory T cells (Treg) in blood, lymphoid organs, and the aorta. Numbers of other immune cells were not affected while expression of inflammatory cytokine genes (e.g. IL-1 beta and IL-6) was increased in the aorta when haematopoietic CD27 was lacking. In vitro, Tregs of CD27-deficient mice showed similar suppressive capacity compared with their wild-type controls and migrated equally towards CCL19 and CCL21. However, thymic Cd27(-/-) Tregs underwent increased apoptosis and expressed fewer markers of proliferation in vivo. Reconstitution of Cd27(-/-)Apoe(-/-) mice with Cd27(+/+)Apoe(-/-) Tregs reversed the increase in atherosclerosis.Conclusion We demonstrate that CD27 co-stimulation increases the number of Tregs and limits lesion development and inflammation in experimental atherosclerosis, particularly during early stages of disease. Thus, our study suggests that promotion of CD27 function may mitigate atherosclerosis.

AB - Aims The co-stimulatory receptor CD27 modulates responses of T cells, B cells, and NK cells. Various T cell subsets participate in atherogenesis. However, the role of CD27 in atherosclerosis remains unexplored.Methods and results Here we investigated the effect of bone marrow-derived and systemic CD27 deficiency in Apolipoprotein E-deficient (Apoe(-/-)) mice in early and advanced stages of atherosclerosis. Lethally-irradiated Apoe(-/-) mice reconstituted with Cd27(-/-)Apoe(-/-) bone marrow and consuming an atherogenic diet displayed a markedly increased plaque size and lesional inflammation compared to mice receiving Cd27(+/+)Apoe(-/-) bone marrow. Accordingly, chow diet-fed Cd27(-/-)Apoe(-/-) mice showed exacerbated lesion development and increased inflammation at the age of 18 weeks. At a more advanced stage of atherosclerosis (28 weeks), lesion size and phenotype did not differ between the two groups. Systemic and bone marrow-derived CD27 deficiency reduced the abundance of regulatory T cells (Treg) in blood, lymphoid organs, and the aorta. Numbers of other immune cells were not affected while expression of inflammatory cytokine genes (e.g. IL-1 beta and IL-6) was increased in the aorta when haematopoietic CD27 was lacking. In vitro, Tregs of CD27-deficient mice showed similar suppressive capacity compared with their wild-type controls and migrated equally towards CCL19 and CCL21. However, thymic Cd27(-/-) Tregs underwent increased apoptosis and expressed fewer markers of proliferation in vivo. Reconstitution of Cd27(-/-)Apoe(-/-) mice with Cd27(+/+)Apoe(-/-) Tregs reversed the increase in atherosclerosis.Conclusion We demonstrate that CD27 co-stimulation increases the number of Tregs and limits lesion development and inflammation in experimental atherosclerosis, particularly during early stages of disease. Thus, our study suggests that promotion of CD27 function may mitigate atherosclerosis.

KW - Atherosclerosis

KW - Inflammation

KW - Regulatory T cells

KW - CD27

KW - ACUTE CORONARY SYNDROMES

KW - DENDRITIC CELLS

KW - CD27-CD70 INTERACTIONS

KW - IMMUNE ACTIVATION

KW - KNOCKOUT MICE

KW - CD70

KW - MAINTENANCE

KW - MECHANISMS

KW - PATHWAY

KW - CD40

U2 - 10.1093/eurheartj/ehx517

DO - 10.1093/eurheartj/ehx517

M3 - Article

C2 - 29045618

SN - 0195-668X

VL - 38

SP - 3590

EP - 3599

JO - European Heart Journal

JF - European Heart Journal

IS - 48

ER -