title: Suppression of expression and function of negative immune regulator PD-1 by certain pattern recognition and cytokine receptor signals associated with immune system danger.
abstract: Stimulation of certain cytokine and pattern recognition receptors enhances adaptive immune responses, and in chronic situations, may play a role in the loss of self-tolerance. We hypothesized that in addition to upregulating positive immune receptors (i.e. co-stimulatory molecules), certain cytokine and pattern recognition signals might downregulate negative immune receptors, removing a potential barrier to lymphocyte responsiveness. The newly identified CD28 family member Programmed Death-1 (PD-1) is an inhibitory receptor involved in peripheral tolerance, as evidenced by the frank autoimmunity and autoantibody formation found in PD-1-deficient mice. Here we report that antigen-receptor induced PD-1 expression on murine B cells is markedly reduced by certain signals associated with immune system danger, including LPS, CpG oligodeoxynucleotides and several pro-inflammatory cytokines, through distinct signaling pathways. We further report for the first time that engagement of PD-1 inhibits cell cycle progression in primary B cells and that modulation of PD-1 expression by CpG or IL-4 significantly reverses such inhibition. Our data suggest a novel mechanism for enhancement of normal immune responses and disruption of normal tolerance mechanisms.
authors.affiliation: Departments of Medicine, Boston University School of Medicine, Boston University Medical Center, MA 02118, USA.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zhong
authors.forename: Chunyan
authors.initials: C
authors.lastname: Bai
authors.forename: Wenda
authors.initials: W
authors.lastname: Gao
authors.forename: Terry B
authors.initials: TB
authors.lastname: Strom
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Rothstein
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation; D001402:B-Lymphocytes / Q000276:immunology*; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D061026:Programmed Cell Death 1 Receptor; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D017634:Self Tolerance / Q000235:genetics / Q000276:immunology*
chemical_list: D000943:Antigens, Differentiation; D016207:Cytokines; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011947:Receptors, Antigen, B-Cell