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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD / immunology
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Antigens, CD / metabolism
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Antigens, Surface / immunology*
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Antigens, Surface / metabolism
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Apoptosis Regulatory Proteins / immunology*
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Apoptosis Regulatory Proteins / metabolism
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B7-1 Antigen / immunology*
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B7-1 Antigen / metabolism
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B7-H1 Antigen
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CTLA-4 Antigen
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Cell Movement
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Dendritic Cells / immunology
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Diabetes Mellitus, Experimental / immunology
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Diabetes Mellitus, Experimental / metabolism
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Diabetes Mellitus, Type 1 / immunology
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Diabetes Mellitus, Type 1 / metabolism
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Immune Tolerance*
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Islets of Langerhans / immunology
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Islets of Langerhans / metabolism
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Islets of Langerhans Transplantation
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Lymphocyte Activation
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Membrane Glycoproteins / immunology*
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Inbred NOD
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Mice, Transgenic
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Peptides / immunology*
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Peptides / metabolism
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Programmed Cell Death 1 Receptor
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Receptors, Antigen, T-Cell / immunology*
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Signal Transduction / immunology*
Substances
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Antigens, CD
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Antigens, Surface
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Apoptosis Regulatory Proteins
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B7-1 Antigen
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B7-H1 Antigen
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CTLA-4 Antigen
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Cd274 protein, mouse
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Ctla4 protein, mouse
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Membrane Glycoproteins
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Pdcd1 protein, mouse
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Peptides
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Programmed Cell Death 1 Receptor
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Receptors, Antigen, T-Cell