Article abstract
Nature Immunology 10, 1185 - 1192 (2009)
Published online: 27 September 2009 | doi:10.1038/ni.1790
Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR–induced stop signal
Brian T Fife1,2, Kristen E Pauken2, Todd N Eagar1,3, Takashi Obu2, Jenny Wu1, Qizhi Tang1,4, Miyuki Azuma5, Matthew F Krummel6 & Jeffrey A Bluestone1
Abstract
Programmed death 1 (PD-1) is an inhibitory molecule expressed on activated T cells; however, the biological context in which PD-1 controls T cell tolerance remains unclear. Using two-photon laser-scanning microscopy, we show here that unlike naive or activated islet antigen–specific T cells, tolerized islet antigen–specific T cells moved freely and did not swarm around antigen-bearing dendritic cells (DCs) in pancreatic lymph nodes. Inhibition of T cell antigen receptor (TCR)-driven stop signals depended on continued interactions between PD-1 and its ligand, PD-L1, as antibody blockade of PD-1 or PD-L1 resulted in lower T cell motility, enhanced T cell–DC contacts and caused autoimmune diabetes. Blockade of the immunomodulatory receptor CTLA-4 did not alter T cell motility or abrogate tolerance. Thus, PD-1–PD-L1 interactions maintain peripheral tolerance by mechanisms fundamentally distinct from those of CTLA-4.
- UCSF Diabetes Center, Department of Medicine, University of California, San Francisco, California, USA.
- Department of Medicine, Center for Immunology, University of Minnesota, Minneapolis, Minnesota, USA.
- Department of Neurology, University of Texas Southwestern, Dallas, Texas, USA.
- Department of Surgery, University of California, San Francisco, California, USA.
- Department of Molecular Immunology, Tokyo Medical and Dental University, Tokyo, Japan.
- Department of Pathology, University of California, San Francisco, California, USA.
Correspondence to: Brian T Fife1,2 e-mail: bfife@umn.edu
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