1. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal
- Author
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Fife, Brian T, Pauken, Kristen E, Eagar, Todd N, Obu, Takashi, Wu, Jenny, Tang, Qizhi, Azuma, Miyuki, Krummel, Matthew F, and Bluestone, Jeffrey A
- Subjects
Programmed Cell Death 1 Receptor ,Immunology ,Islets of Langerhans Transplantation ,Neurodegenerative ,Inbred C57BL ,Lymphocyte Activation ,Transgenic ,B7-H1 Antigen ,Islets of Langerhans ,Mice ,Experimental ,CD80 ,Cell Movement ,Receptors ,Diabetes Mellitus ,Immune Tolerance ,CD274 ,Animals ,2.1 Biological and endogenous factors ,CTLA-4 Antigen ,Antigens ,Aetiology ,Membrane Glycoproteins ,Parkinson's Disease ,Prevention ,Neurosciences ,Dendritic Cells ,T-Cell ,CD ,Brain Disorders ,Surface ,Antigen ,Neurological ,B7-1 Antigen ,Inbred NOD ,Peptides ,Apoptosis Regulatory Proteins ,Type 1 ,Signal Transduction - 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.
- Published
- 2009