PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2.
Programmed death-1 (PD-1) is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptor expressed upon T cell activation. PD-1(-/-) animals develop autoimmune diseases, suggesting an inhibitory role for PD-1 in immune responses. Members of the B7 family, PD-L1 and PD-L2, are ligands for PD-1. This study examines the functional consequences of PD-1:PD-L engagement on murine CD4 and CD8 T cells and shows that these interactions result in inhibition of proliferation and cytokine production. T cells stimulated with anti-CD3/PD-L1.Fc-coated beads display dramatically decreased proliferation and IL-2 production, while CSFE analysis shows fewer cells cycling and a slower division rate. Costimulation with soluble anti-CD28 mAb can overcome PD-1-mediated inhibition by augmenting IL-2 production. However, PD-1:PD-L interactions inhibit IL-2 production even in the presence of costimulation and, thus, after prolonged activation, the PD-1:PD-L inhibitory pathway dominates. Exogenous IL-2 is able to overcome PD-L1-mediated inhibition at all times, indicating that cells maintain IL-2 responsiveness. Experiments using TCR transgenic CD4(+) or CD8(+) T cells stimulated with antigen-presenting cells expressing PD-L1 show that both T cell subsets are susceptible to this inhibitory pathway. However, CD8(+) T cells may be more sensitive to modulation by the PD-1:PD-L pathway because of their intrinsic inability to produce significant levels of IL-2.
Carter
LauraL
L
Wyeth-Genetics Institute, Cambridge, MA 02140, USA. LCarter@genetics.com
Fouser
Lynette A
LA
Jussif
Jason
J
Fitz
Lori
L
Deng
Bija
B
Wood
Clive R
CR
Collins
Mary
M
Honjo
Tasuku
T
Freeman
Gordon J
GJ
Carreno
Beatriz M
BM
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017951:Antigen Presentation; D000954:Antigens, Surface; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002455:Cell Division; D002460:Cell Line; D005260:Female; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D019012:Integrin beta1 / Q000276:immunology; D007376:Interleukin-2 / Q000494:pharmacology / Q000502:physiology*; D007700:Kinetics; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008863:Microspheres; D008969:Molecular Sequence Data; D010455:Peptides / Q000502:physiology*; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D011506:Proteins / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins; D017252:CD3 Complex; C498919:Cd274 protein, mouse; D007141:Immunoglobulin Fc Fragments; D019012:Integrin beta1; D007376:Interleukin-2; D008024:Ligands; 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; D011506:Proteins; D011948:Receptors, Antigen, T-Cell