Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal.
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.
Fife
Brian T
BT
UCSF Diabetes Center, Department of Medicine, University of California, San Francisco, California, USA. bfife@umn.edu
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
D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000954:Antigens, Surface / Q000276:immunology* / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000276:immunology* / Q000378:metabolism; D018122:B7-1 Antigen / Q000276:immunology* / Q000378:metabolism; D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen; D002465:Cell Movement; D003713:Dendritic Cells / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010455:Peptides / Q000276:immunology* / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*
D015703:Antigens, CD; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen; C498919:Cd274 protein, mouse; C556707:Ctla4 protein, mouse; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell