title: Protective role of programmed death 1 ligand 1 (PD-L1)in nonobese diabetic mice: the paradox in transgenic models.
abstract: OBJECTIVE
  Coinhibitory signals mediated via programmed death 1 (PD-1) receptor play a critical role in downregulating immune responses and in maintaining peripheral tolerance. Programmed death 1 ligand 1 (PD-L1), the interacting ligand for PD-1, widely expressed in many cell types, acts as a tissue-specific negative regulator of pathogenic T-cell responses. We investigated the protective potential of PD-L1 on autoimmune diabetes by transgenically overexpressing PD-L1 in pancreatic beta-cells in nonobese diabetic (NOD) mice.
  
  
  METHODS
  We established an insulin promoter-driven murine PD-L1 transgenic NOD mouse model to directly evaluate the protective effect of an organ-specific PD-L1 transgene against autoimmune diabetes. Transgene expression, insulitis, and diabetic incidence were characterized in these transgenic NOD mice. Lymphocyte development, Th1 cells, and regulatory T-cells were analyzed in these transgenic mice; and T-cell proliferation, adoptive transfer, and islet transplantation were performed to evaluate the PD-L1 transgene-mediated immune-protective mechanisms.
  
  
  RESULTS
  The severity of insulitis in these transgenic mice is significantly decreased, disease onset is delayed, and the incidence of diabetes is markedly decreased compared with littermate controls. NOD/SCID mice that received lymphocytes from transgenic mice became diabetic at a slower rate than mice receiving control lymphocytes. Moreover, lymphocytes collected from recipients transferred by lymphocytes from transgenic mice revealed less proliferative potential than lymphocytes obtained from control recipients. Transgenic islets transplanted in diabetic recipients survived moderately longer than control islets.
  
  
  CONCLUSIONS
  Our results demonstrate the protective potential of transgenic PD-L1 in autoimmune diabetes and illustrate its role in downregulating diabetogenic T-cells in NOD mice.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Chia-Jen
authors.initials: CJ
authors.lastname: Wang
authors.forename: Feng-Cheng
authors.initials: FC
authors.lastname: Chou
authors.forename: Chi-Hong
authors.initials: CH
authors.lastname: Chu
authors.forename: Jen-Chine
authors.initials: JC
authors.lastname: Wu
authors.forename: Shih-Hua
authors.initials: SH
authors.lastname: Lin
authors.forename: Deh-Ming
authors.initials: DM
authors.lastname: Chang
authors.forename: Huey-Kang
authors.initials: HK
authors.lastname: Sytwu
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018122:B7-1 Antigen / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D060890:B7-H1 Antigen; D002455:Cell Division; D003001:Cloning, Molecular; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D005260:Female; D006946:Hyperinsulinism / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD / Q000235:genetics; D016513:Mice, SCID; D008822:Mice, Transgenic; D010179:Pancreas / Q000473:pathology; D010455:Peptides / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D010957:Plasmids; D016133:Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; D010455:Peptides