Protective Role of Programmed Death 1 Ligand 1 (PD-L1)in Nonobese Diabetic Mice

The Paradox in Transgenic Models

  1. Chia-Jen Wang1,
  2. Feng-Cheng Chou1,
  3. Chi-Hong Chu2,
  4. Jen-Chine Wu1,
  5. Shih-Hua Lin3,
  6. Deh-Ming Chang3 and
  7. Huey-Kang Sytwu1456
  1. 1Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, China
  2. 2Department of Surgery, National Defense Medical Center, Taipei, Taiwan, China
  3. 3Department of Internal Medicine, National Defense Medical Center, Taipei, Taiwan, China
  4. 4Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, China
  5. 5Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan, China
  6. 6Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, China
  1. Corresponding author: Huey-Kang Sytwu, sytwu{at}


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 β-cells in nonobese diabetic (NOD) mice.

RESEARCH DESIGN AND 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.


  • Published ahead of print at on 16 April 2008.

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    • Accepted April 11, 2008.
    • Received September 5, 2007.
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  1. Diabetes vol. 57 no. 7 1861-1869
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