title: Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production.
abstract: Programmed death-1 ligand (PD-L)1 and PD-L2 are ligands for programmed death-1 (PD-1), a member of the CD28/CTLA4 family expressed on activated lymphoid cells. PD-1 contains an immunoreceptor tyrosine-based inhibitory motif and mice deficient in PD-1 develop autoimmune disorders suggesting a defect in peripheral tolerance. Human PD-L1 and PD-L2 are expressed on immature dendritic cells (iDC) and mature dendritic cells (mDC), IFN-gamma-treated monocytes, and follicular dendritic cells. Using mAbs, we show that blockade of PD-L2 on dendritic cells results in enhanced T cell proliferation and cytokine production, including that of IFN-gamma and IL-10, while blockade of PD-L1 results in similar, more modest, effects. Blockade of both PD-L1 and PD-L2 showed an additive effect. Both whole mAb and Fab enhanced T cell activation, showing that PD-L1 and PD-L2 function to inhibit T cell activation. Enhancement of T cell activation was most pronounced with weak APC, such as iDCs and IL-10-pretreated mDCs, and less pronounced with strong APC such as mDCs. These data are consistent with the hypothesis that iDC have a balance of stimulatory vs inhibitory molecules that favors inhibition, and indicate that PD-L1 and PD-L2 contribute to the poor stimulatory capacity of iDC. PD-L1 expression differs from PD-L2 in that PD-L1 is expressed on activated T cells, placental trophoblasts, myocardial endothelium, and cortical thymic epithelial cells. In contrast, PD-L2 is expressed on placental endothelium and medullary thymic epithelial cells. PD-L1 is also highly expressed on most carcinomas but minimally expressed on adjacent normal tissue suggesting a role in attenuating antitumor immune responses.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Brown
authors.forename: David M
authors.initials: DM
authors.lastname: Dorfman
authors.forename: Feng-Rong
authors.initials: FR
authors.lastname: Ma
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Sullivan
authors.forename: Oliver
authors.initials: O
authors.lastname: Munoz
authors.forename: Clive R
authors.initials: CR
authors.lastname: Wood
authors.forename: Edward A
authors.initials: EA
authors.lastname: Greenfield
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
mesh_terms: D000818:Animals; D015703:Antigens, CD; D000954:Antigens, Surface; D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001667:Binding, Competitive / Q000276:immunology; D001798:Blood Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009928:Organ Specificity / Q000276:immunology; D010455:Peptides / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism*; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D011506:Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: 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; C498919:Cd274 protein, mouse; D016207:Cytokines; D007140:Immunoglobulin Fab Fragments; 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; D011506:Proteins