期刊
BLOOD
卷 122, 期 17, 页码 3062-3073出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2013-05-500801
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资金
- National Institutes of Health Research Program [P01]
- National Institute of Allergy and Infectious Diseases [AI056299]
- Institute of Allergy and Infectious Diseases [AI034495]
- Heart, Lung and Blood Institute [HL056067, HL049997]
- National Cancer Institute [CA072669]
- National Center for Research Resources Shared Instrumentation Grant [1 S10 RR16851]
- Grants-in-Aid for Scientific Research [23249082] Funding Source: KAKEN
Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, play an important role in the maintenance of peripheral tolerance. We explored the role of PD-1 ligands in regulating graft-versus-host disease (GVHD). Both PD-L1 and PD-L2 expression were upregulated in the spleen, liver, colon, and ileum of GVHD mice. Whereas PD-L2 expression was limited to hematopoietic cells, hematopoietic and endothelial cells expressed PD-L1. PD-1/PD-L1, but not PD-1/PD-L2, blockade markedly accelerated GVHD-induced lethality. Chimera studies suggest that PD-L1 expression on host parenchymal cells is more critical than hematopoietic cells in regulating acute GVHD. Rapid mortality onset in PD-L1-deficient hosts was associated with increased gut T-cell homing and loss of intestinal epithelial integrity, along with increased donor T-cell proliferation, activation, Th1 cytokine production, and reduced apoptosis. Bioenergetics profile analysis of proliferating alloreactive donor T-cells demonstrated increased aerobic glycolysis and oxidative phosphorylation in PD-L1-deficient hosts. Donor T-cells exhibited a hyperpolarized mitochondrial membrane potential, increased superoxide production, and increased expression of a glucose transporter in PD-L1-deficient hosts. Taken together, these data provide new insight into the differential roles of host PD-L1 and PD-L2 and their associated cellular and metabolic mechanisms controlling acute GVHD.
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