Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal.

Full 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.

Author information

Author/s: Fife, Brian T (BT); Pauken, Kristen E (KE); Eagar, Todd N (TN); Obu, Takashi (T); Wu, Jenny (J); Tang, Qizhi (Q); Azuma, Miyuki (M); Krummel, Matthew F (MF); Bluestone, Jeffrey A (JA);

Affiliation: UCSF Diabetes Center, Department of Medicine, University of California, San Francisco, California, USA. bfife(-atsign-)umn.edu

Grants: AI35297 (Agency:NIAID NIH HHS) ; P30 DK63720 (Agency:NIDDK NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Nature immunology (Nat Immunol), published in United States. (Language: eng)

Reference: 2009-Nov; vol 10 (issue 11) : pp 1185-92

Dates: Created 2009/10/20; Completed 2009/10/23;

PMID: 19783989, status: MEDLINE (last retrieval date: 10/23/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals
Antigens, CD - immunology; metabolism
Antigens, CD80 - immunology; metabolism
Antigens, Surface - immunology; metabolism
Apoptosis Regulatory Proteins - immunology; metabolism
Cell Movement
Dendritic Cells - immunology
Diabetes Mellitus, Experimental - immunology; metabolism
Diabetes Mellitus, Type 1 - immunology; metabolism
Immune Tolerance
Islets of Langerhans - immunology; metabolism

Islets of Langerhans - immunology; metabolism
Islets of Langerhans Transplantation
Lymphocyte Activation
Membrane Glycoproteins - immunology; metabolism
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Transgenic
Peptides - immunology; metabolism
Receptors, Antigen, T-Cell - immunology
Signal Transduction - immunology

Associated Chemicals: Antigens, CD (0) ; Antigens, CD80 (0) ; Antigens, Surface (0) ; Apoptosis Regulatory Proteins (0) ; Membrane Glycoproteins (0) ; Pdcd1 protein, mouse (0) ; Pdcd1lg1 protein, mouse (0) ; Peptides (0) ; Receptors, Antigen, T-Cell (0) ; cytotoxic T-lymphocyte antigen 4 (0)

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