Role of PD-1 and its ligand, B7-H1, in early fate decisions of CD8 T cells.
Expression of the PD-1 receptor on T cells has been shown to provide an important inhibitory signal that down-modulates peripheral effector responses in normal tissues and tumors. Furthermore, PD-1 up-regulation on chronically activated T cells can maintain them in a partially reversible inactive state. The function of PD-1 in the very early stages of T-cell response to antigen in vivo has not been fully explored. In this study, we evaluate the role of PD-1 and its 2 B7 family ligands, B7-H1 (PD-L1) and B7-DC (PD-L2), in early fate decisions of CD8 T cells. We show that CD8 T cells specific for influenza hemagglutinin (HA) expressed as a self-antigen become functionally tolerized and express high levels of surface PD-1 by the time of their first cell division. Blockade of PD-1 or B7-H1, but not B7-DC, at the time of self-antigen encounter mitigates tolerance induction and results in CD8 T-cell differentiation into functional cytolytic T lymphocytes (CTLs). These findings demonstrate that, in addition to modulating effector functions in the periphery, B7-H1:PD-1 interactions regulate early T-cell-fate decisions.
Goldberg
Monica V
MV
Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA.
Maris
Charles H
CH
Hipkiss
Edward L
EL
Flies
Andrew S
AS
Zhen
Lijie
L
Tuder
Rubin M
RM
Grosso
Joseph F
JF
Harris
Timothy J
TJ
Getnet
Derese
D
Whartenby
Katharine A
KA
Brockstedt
Dirk G
DG
Dubensky
Thomas W
TW
Chen
Lieping
L
Pardoll
Drew M
DM
Drake
Charles G
CG
D000818:Animals; D000954:Antigens, Surface / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D001324:Autoantigens; D018122:B7-1 Antigen / Q000502:physiology*; D060890:B7-H1 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D010455:Peptides / Q000502:physiology*; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D011485:Protein Binding; D017634:Self Tolerance; D013602:T-Lymphocytes, Cytotoxic
D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D001324:Autoantigens; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor