PD-L2 is a second ligand for PD-1 and inhibits T cell activation.
Programmed death I (PD-I)-deficient mice develop a variety of autoimmune-like diseases, which suggests that this immunoinhibitory receptor plays an important role in tolerance. We identify here PD-1 ligand 2 (PD-L2) as a second ligand for PD-1 and compare the function and expression of PD-L1 and PD-L2. Engagement of PD-1 by PD-L2 dramatically inhibits T cell receptor (TCR)-mediated proliferation and cytokine production by CD4+ T cells. At low antigen concentrations, PD-L2-PD-1 interactions inhibit strong B7-CD28 signals. In contrast, at high antigen concentrations, PD-L2-PD-1 interactions reduce cytokine production but do not inhibit T cell proliferation. PD-L-PD-1 interactions lead to cell cycle arrest in G0/G1 but do not increase cell death. In addition, ligation of PD-1 + TCR leads to rapid phosphorylation of SHP-2, as compared to TCR ligation alone. PD-L expression was up-regulated on antigen-presenting cells by interferon gamma treatment and was also present on some normal tissues and tumor cell lines. Taken together, these studies show overlapping functions of PD-L1 and PD-L2 and indicate a key role for the PD-L-PD-1 pathway in regulatingT cell responses.
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Y
Y
Latchman
C R
CR
Wood
T
T
Chernova
D
D
Chaudhary
M
M
Borde
I
I
Chernova
Y
Y
Iwai
A J
AJ
Long
J A
JA
Brown
R
R
Nunes
E A
EA
Greenfield
K
K
Bourque
V A
VA
Boussiotis
L L
LL
Carter
B M
BM
Carreno
N
N
Malenkovich
H
H
Nishimura
T
T
Okazaki
T
T
Honjo
A H
AH
Sharpe
G J
GJ
Freeman
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD; D000954:Antigens, Surface / Q000276:immunology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins; D018106:CD28 Antigens / Q000276:immunology; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D008024:Ligands; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection
D015703:Antigens, CD; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins; C423236:CD274 protein, human; D018106:CD28 Antigens; C498919:Cd274 protein, mouse; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; C105992:PDCD1 protein, human; C556977:PDCD1LG2 protein, human; C491383:Pdcd1 protein, mouse; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell