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Winkels, Holger; Meiler, Svenja; Lievens, Dirk; Engel, David; Spitz, Charlotte; Bürger, Christina; Beckers, Linda; Dandl, Angelika; Reim, Sigrid; Ahmadsei, Maiwand; Hartwig, Helene; Holdt, Lesca M.; Hristov, Michael; Megens, Remco T. A.; Schmitt, Martin M.; Biessen, Eric A.; Borst, Jannie; Faussner, Alexander; Weber, Christian; Lutgens, Esther; Gerdes, Norbert (2017): CD27 co-stimulation increases the abundance of regulatory T cells and reduces atherosclerosis in hyperlipidaemic mice. In: European Heart Journal, Vol. 38, No. 48: 3590-U42
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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.