T-cell co-stimulation by CD28–CD80/86 and its negative regulator CTLA-4 strongly influence accelerated atherosclerosis development M.M. Ewing, J.C. Karper,

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T-cell co-stimulation by CD28–CD80/86 and its negative regulator CTLA-4 strongly influence accelerated atherosclerosis development M.M. Ewing, J.C. Karper, S. Abdul, R.C.M. de Jong, H.A.B. Peters, M.R. de Vries, A. Redeker, J. Kuiper, R.E.M. Toes, R. Arens, J.W. Jukema, P.H.A. Quax International Journal of Cardiology Volume 168, Issue 3, Pages 1965-1974 (October 2013) DOI: 10.1016/j.ijcard.2012.12.085 Copyright © 2013 Elsevier Ireland Ltd Terms and Conditions

Fig. 1 Reduced vascular remodeling in CD4−/− and CD80−/−CD86−/− and abatacept-treated mice. Representative cross-sections of cuffed-femoral arteries of CD4−/−CD80−/−CD86−/− and abatacept-treated mice (A) after 21days (hematoxylin–phloxine–saffron (HPS) and Weigert's elastin staining, 80×, arrows indicate internal elastic laminae). Quantification of intimal thickening (μm2) (B), intima/media ratio (C) and luminal stenosis (%) (D). Representative cross-sections of cuffed-femoral arteries of CD4−/−CD80−/−CD86−/− and abatacept-treated mice (E) after 21days (α-SMC actin and Sirius Red collagen staining, 80×). Quantification of relative medial SMC (F) and collagen (G) areas (%) and intimal SMC (H) and collagen (I) areas (%). Horizontal bars indicate median values, n=10. *p<0.05, **p<0.01. International Journal of Cardiology 2013 168, 1965-1974DOI: (10.1016/j.ijcard.2012.12.085) Copyright © 2013 Elsevier Ireland Ltd Terms and Conditions

Fig. 1 Reduced vascular remodeling in CD4−/− and CD80−/−CD86−/− and abatacept-treated mice. Representative cross-sections of cuffed-femoral arteries of CD4−/−CD80−/−CD86−/− and abatacept-treated mice (A) after 21days (hematoxylin–phloxine–saffron (HPS) and Weigert's elastin staining, 80×, arrows indicate internal elastic laminae). Quantification of intimal thickening (μm2) (B), intima/media ratio (C) and luminal stenosis (%) (D). Representative cross-sections of cuffed-femoral arteries of CD4−/−CD80−/−CD86−/− and abatacept-treated mice (E) after 21days (α-SMC actin and Sirius Red collagen staining, 80×). Quantification of relative medial SMC (F) and collagen (G) areas (%) and intimal SMC (H) and collagen (I) areas (%). Horizontal bars indicate median values, n=10. *p<0.05, **p<0.01. International Journal of Cardiology 2013 168, 1965-1974DOI: (10.1016/j.ijcard.2012.12.085) Copyright © 2013 Elsevier Ireland Ltd Terms and Conditions

Fig. 2 Abatacept prevents accelerated atherosclerosis in hypercholesterolemic mice. Representative cross-sections of cuffed-femoral arteries of hypercholesterolemic ApoE3*Leiden mice following vehicle or abatacept-treatment (A) after 14days (HPS and Weigert's elastin staining, 80×, arrows in inserts indicate internal elastic laminae). Quantification of intimal thickening (μm2) (B), medial area (μm2) (C), intima/media ratio (D) and luminal stenosis (%) (E). Horizontal bars indicate median values, n=10. *p<0.05. International Journal of Cardiology 2013 168, 1965-1974DOI: (10.1016/j.ijcard.2012.12.085) Copyright © 2013 Elsevier Ireland Ltd Terms and Conditions

Fig. 3 Abatacept positively affects accelerated atherosclerotic lesion composition. Representative cross-sections of cuffed-femoral arteries of ApoE3*Leiden mice following vehicle or abatacept-treatment (A) after 14days (leukocyte, macrophage and α-SMC actin staining, 80×). Quantification of relative medial leukocyte (B), macrophage (D) and SMC (F) areas (%) and intimal leukocyte (C), macrophage (E) and SMC (G) areas (%) and intimal CD3 (n) (H) and MMP-9 (n) (I), as well as adventitial CD3 (n) (J) and MMP-9 cells (n) (K). Horizontal bars indicate median values, n=10. *p<0.05, **p<0.01. (L) T-cell CTLA-4 and CD4 expression throughout the vessel wall of ApoE3*Leiden mice in time before and 3days and 14days after surgery (CTLA-4 and CD4 staining, 80×, arrows in inserts indicate positive staining). International Journal of Cardiology 2013 168, 1965-1974DOI: (10.1016/j.ijcard.2012.12.085) Copyright © 2013 Elsevier Ireland Ltd Terms and Conditions

Fig. 3 Abatacept positively affects accelerated atherosclerotic lesion composition. Representative cross-sections of cuffed-femoral arteries of ApoE3*Leiden mice following vehicle or abatacept-treatment (A) after 14days (leukocyte, macrophage and α-SMC actin staining, 80×). Quantification of relative medial leukocyte (B), macrophage (D) and SMC (F) areas (%) and intimal leukocyte (C), macrophage (E) and SMC (G) areas (%) and intimal CD3 (n) (H) and MMP-9 (n) (I), as well as adventitial CD3 (n) (J) and MMP-9 cells (n) (K). Horizontal bars indicate median values, n=10. *p<0.05, **p<0.01. (L) T-cell CTLA-4 and CD4 expression throughout the vessel wall of ApoE3*Leiden mice in time before and 3days and 14days after surgery (CTLA-4 and CD4 staining, 80×, arrows in inserts indicate positive staining). International Journal of Cardiology 2013 168, 1965-1974DOI: (10.1016/j.ijcard.2012.12.085) Copyright © 2013 Elsevier Ireland Ltd Terms and Conditions

Fig. 4 Abatacept prevents systemic CD4 T-cell activation in ApoE3*Leiden mice. Abatacept did not affect total CD4 splenic T-cell count (absolute cells) 14days after surgery (A). T-cells were analyzed using multiparametric flow cytometry and gated for 7AAD−, CD3+ and CD4+ markers and subsequently for either KLRG1+, PD1+, CD69+, CTLA-4+ or CD25+ and FoxP3+ expression and are displayed in dot plots (D and G). Abatacept reduced CD69+ (B), PD1+ (C), KLRG1+ (E) and CTLA-4+ (F) activated CD4 T-cell fractions (%), together with CD25+FoxP3+ regulatory (H) CD4 T-cell fractions (%). Horizontal bars indicate median values, n=5. *p<0.05, **p<0.01. International Journal of Cardiology 2013 168, 1965-1974DOI: (10.1016/j.ijcard.2012.12.085) Copyright © 2013 Elsevier Ireland Ltd Terms and Conditions

Fig. 5 Profound CD4 T-cell contribution to post-interventional accelerated atherosclerosis development. (A) Positive correlation between KLRG1+ CD4 T-cell fractions (%) and intimal thickening (μm2) (n=6). Abatacept did not affect CD4 regulatory T-cell: effector T-cell ratio (B). Plasma IFNγ (pg/ml) was reduced after 14days following abatacept-treatment (C), while plasma IL-10 (pg/ml) was upregulated (D). Horizontal bars indicate median values, n=10. n.d. non-detectable. *p<0.05, **p<0.01. International Journal of Cardiology 2013 168, 1965-1974DOI: (10.1016/j.ijcard.2012.12.085) Copyright © 2013 Elsevier Ireland Ltd Terms and Conditions

Fig. 6 CTLA-4 blockade exacerbates accelerated atherosclerosis development. Representative cross-sections of cuffed-femoral arteries of hypercholesterolemic ApoE3*Leiden mice following isotype antibody or anti-CTLA-4 IgG-treatment (A) after 14days (HPS, Weigert's elastin and CD3 staining, 80–160×, arrows in insets indicate internal elastic laminae and CD3+ T-cells). Quantification of intimal thickening (μm2) (B), intima/media ratio (C), luminal stenosis (%) (D) and luminal area (μm2) (E). Quantification of intimal CD3 (n) (F) and adventitial CD3 (n) (G) cells. Horizontal bars indicate median values, n=10. *p<0.05, **p<0.01. International Journal of Cardiology 2013 168, 1965-1974DOI: (10.1016/j.ijcard.2012.12.085) Copyright © 2013 Elsevier Ireland Ltd Terms and Conditions