Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation.
PD-1 is an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells. Mice deficient in PD-1 exhibit a breakdown of peripheral tolerance and demonstrate multiple autoimmune features. We report here that the ligand of PD-1 (PD-L1) is a member of the B7 gene family. Engagement of PD-1 by PD-L1 leads to the inhibition of T cell receptor-mediated lymphocyte proliferation and cytokine secretion. In addition, PD-1 signaling can inhibit at least suboptimal levels of CD28-mediated costimulation. PD-L1 is expressed by antigen-presenting cells, including human peripheral blood monocytes stimulated with interferon gamma, and activated human and murine dendritic cells. In addition, PD-L1 is expressed in nonlymphoid tissues such as heart and lung. The relative levels of inhibitory PD-L1 and costimulatory B7-1/B7-2 signals on antigen-presenting cells may determine the extent of T cell activation and consequently the threshold between tolerance and autoimmunity. PD-L1 expression on nonlymphoid tissues and its potential interaction with PD-1 may subsequently determine the extent of immune responses at sites of inflammation.
Freeman
G J
GJ
Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Long
A J
AJ
Iwai
Y
Y
Bourque
K
K
Chernova
T
T
Nishimura
H
H
Fitz
L J
LJ
Malenkovich
N
N
Okazaki
T
T
Byrne
M C
MC
Horton
H F
HF
Fouser
L
L
Carter
L
L
Ling
V
V
Bowman
M R
MR
Carreno
B M
BM
Collins
M
M
Wood
C R
CR
Honjo
T
T
D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD / Q000145:classification / Q000235:genetics / Q000276:immunology*; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen / Q000145:classification / Q000235:genetics / Q000276:immunology*; D051940:B7-2 Antigen; D001483:Base Sequence; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002455:Cell Division; D018076:DNA, Complementary; D015870:Gene Expression; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000145:classification / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology
D015703:Antigens, CD; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D017252:CD3 Complex; C497964:CD86 protein, human; C497965:Cd86 protein, mouse; D018076:DNA, Complementary; D008024:Ligands; D008562:Membrane Glycoproteins; C105992:PDCD1 protein, human; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor