PD-1, but Not PD-L1, Expressed by Islet-Reactive CD4+ T Cells Suppresses Infiltration of the Pancreas During Type 1 Diabetes

  1. Brian T. Fife1
  1. 1Department of Medicine, Center for Immunology, University of Minnesota, Minneapolis, Minnesota
  2. 2Department of Microbiology, Center for Immunology, University of Minnesota, Minneapolis, Minnesota
  3. 3Department of Molecular Immunology, Tokyo Medical and Dental University, Tokyo, Japan
  1. Corresponding author: Brian T. Fife, bfife{at}


The inhibitory receptor programmed death-1 (PD-1) constrains type 1 diabetes (T1D) in the nonobese diabetic (NOD) mouse. However, how PD-1 influences diabetogenic CD4+ T cells during natural diabetes is not fully understood. To address this question, we developed a novel model to investigate antigen-specific CD4+ T cells under physiological conditions in vivo. We transferred a low number of naïve CD4+ T cells from the BDC2.5 mouse into prediabetic NOD mice to mimic a physiological precursor frequency and allowed the cells to become primed by endogenous autoantigen. Transferred BDC2.5 T cells became activated, differentiated into T-bet+ IFN-γ–producing cells, and infiltrated the pancreas. In this model, loss of PD-1, but not programmed death ligand-1 (PD-L1), on the antigen-specific CD4+ T cell resulted in increased cell numbers in the spleen, pancreas-draining lymph node, and pancreas. PD-1 deficiency also increased expression of the chemokine receptor CXCR3. Lastly, histological data showed that a loss of PD-1 caused BDC2.5 cells to penetrate deep into the islet core, resulting in conversion from peri-insulitis to destructive insulitis. These data support a model by which PD-1 regulates islet-reactive CD4+ T cells in a cell intrinsic manner by suppressing proliferation, inhibiting infiltration of the pancreas, and limiting diabetes.


  • Received October 24, 2012.
  • Accepted March 21, 2013.

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