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PMID: 19783989 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature immunology ·Vol. 10 ·No. 11 ·2009-11-00 ·Pages 1185-92

Fife BT, Pauken KE, Eagar TN, Obu T, Wu J, Tang Q, Azuma M, Krummel MF, Bluestone JA

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.

MeSH Terms
Animals Antigens, CD/immunology,metabolism Antigens, Surface/immunology,metabolism Apoptosis Regulatory Proteins/immunology,metabolism B7-1 Antigen/immunology,metabolism B7-H1 Antigen CTLA-4 Antigen 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 Transplantation Lymphocyte Activation Membrane Glycoproteins/immunology,metabolism Mice Mice, Inbred C57BL Mice, Inbred NOD Mice, Transgenic Peptides/immunology,metabolism Programmed Cell Death 1 Receptor Receptors, Antigen, T-Cell/immunology Signal Transduction/immunology
Chemicals
Antigens, CD Antigens, Surface Apoptosis Regulatory Proteins B7-1 Antigen B7-H1 Antigen CTLA-4 Antigen Cd274 protein, mouse Ctla4 protein, mouse Membrane Glycoproteins Pdcd1 protein, mouse Peptides Programmed Cell Death 1 Receptor Receptors, Antigen, T-Cell
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Fife Brian T
UCSF Diabetes Center, Department of Medicine, University of California, San Francisco, California, USA. bfife@umn.edu
Pauken Kristen E
Eagar Todd N
Obu Takashi
Wu Jenny
Tang Qizhi
Azuma Miyuki
Krummel Matthew F
Bluestone Jeffrey A
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Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2916
DOI
10.1038/ni.1790
Email
bfife@umn.edu
Published
2009-11-00
Epub
2009-00-27
Pages
1185-92
Language
English
Region
United States
NLM ID
100941354
PMCID
PMC2778301
Subset
IM
Grants
NIDDK NIH HHS · P30 DK063720 · United States
NIAID NIH HHS · P01 AI035297 · United States
NIDDK NIH HHS · P30 DK63720 · United States
NIDDK NIH HHS · P30 DK063720-019002 · United States
NIAID NIH HHS · AI35297 · United States
NIAID NIH HHS · P01 AI035297-170006 · United States
Corrections
CommentIn
PMID: 20218851
External Links
PubMed source DOI: 10.1038/ni.1790 PMC Full Text View journal details
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