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Endothelial Programmed Death-1 Ligand 1 (PD-L 1) Regulates CD 8+ T-Cell–Mediated Injury in the Endothelial Programmed Death-1 Ligand 1 (PD-L 1) Regulates CD 8+ T-Cell–Mediated Injury in the Heart by Nir Grabie, Israel Gotsman, Rosa Da. Costa, Hong Pang, George Stavrakis, Manish J. Butte, Mary E. Keir, Gordon J. Freeman, Arlene H. Sharpe, and Andrew H. Lichtman Circulation Volume 116(18): 2062 -2071 October 30, 2007 Copyright © American Heart Association, Inc. All rights reserved.

Figure 1. CMy-m. Ova mice develop transient cardiac injury after adoptive transfer of 25× Figure 1. CMy-m. Ova mice develop transient cardiac injury after adoptive transfer of 25× 103 OT-I CTLs. A, CMy-m. Ova mice were injected with OT-I CTLs (25× 103) and euthanized at 5 and 11 days after CTL transfer. Nir Grabie et al. Circulation. 2007; 116: 2062 -2071 Copyright © American Heart Association, Inc. All rights reserved.

Figure 2. PD-L 1 is upregulated in the heart during CTL-induced cardiac injury. Nir Figure 2. PD-L 1 is upregulated in the heart during CTL-induced cardiac injury. Nir Grabie et al. Circulation. 2007; 116: 2062 -2071 Copyright © American Heart Association, Inc. All rights reserved.

Figure 3. IFN-γ signaling is critical for upregulation of endothelial PD-L 1 during CTL-induced Figure 3. IFN-γ signaling is critical for upregulation of endothelial PD-L 1 during CTL-induced cardiac injury. Nir Grabie et al. Circulation. 2007; 116: 2062 -2071 Copyright © American Heart Association, Inc. All rights reserved.

Figure 4. PD-L 1 regulates PMN infiltration and prevents lethal cardiac injury. Nir Grabie Figure 4. PD-L 1 regulates PMN infiltration and prevents lethal cardiac injury. Nir Grabie et al. Circulation. 2007; 116: 2062 -2071 Copyright © American Heart Association, Inc. All rights reserved.

Figure 5. Treatment with anti-PD-L 1 blocking antibody increases susceptibility of wild-type CMym. Ova Figure 5. Treatment with anti-PD-L 1 blocking antibody increases susceptibility of wild-type CMym. Ova mice to OT-I–mediated myocarditis. Nir Grabie et al. Circulation. 2007; 116: 2062 -2071 Copyright © American Heart Association, Inc. All rights reserved.

Figure 6. PD-1 ligand expression on bone marrow (BM)–derived cells fails to protect PD-L Figure 6. PD-1 ligand expression on bone marrow (BM)–derived cells fails to protect PD-L 1/2−/− hearts from CTL-mediated injury. Nir Grabie et al. Circulation. 2007; 116: 2062 -2071 Copyright © American Heart Association, Inc. All rights reserved.

Figure 7. PMN depletion reverses the increased lethality of myocarditis caused by PD-L 1/2 Figure 7. PMN depletion reverses the increased lethality of myocarditis caused by PD-L 1/2 deficiency. Nir Grabie et al. Circulation. 2007; 116: 2062 -2071 Copyright © American Heart Association, Inc. All rights reserved.