title: NF-κB regulates PD-1 expression in macrophages.
abstract: Programmed cell death-1 (PD-1) is responsible for T cell exhaustion during chronic viral infections and is expressed on a variety of immune cells following activation. Despite its importance, the mechanisms that regulate PD-1 in cell types other than CD8 T cells are poorly defined. In this study, the molecular mechanisms for inducing PD-1 expression in CD4 T cells, macrophages, and B cells were explored. In CD4 T cells, PD-1 induction following TCR stimulation required NFAT, as the calcineurin/NFAT pathway inhibitor cyclosporin A was able to block PD-1 induction in a manner similar to that seen in CD8 T cells. In contrast, LPS but not PMA and ionomycin stimulation was able to induce PD-1 expression in macrophages in a manner insensitive to cyclosporin A-mediated inhibition. B cells could use both pathways, although the levels of PD-1 expression were highest with PMA and ionomycin. An NF-κB binding site located upstream of the gene in conserved region C was required for NF-κB-dependent PD-1 gene activation in macrophages. Chromatin immunoprecipitation showed NF-κB p65 binding to this region following stimulation of macrophages with LPS. PD-1 induction was associated with histone modifications characteristic of accessible chromatin; however, in contrast to CD8 T cells, conserved region B in macrophages did not lose CpG methylation upon stimulation and PD-1 expression. The linkage of TLR/NF-κB signaling to the induction of PD-1 suggests the possibility of an opportunistic advantage to microbial infections in manipulating immune inhibitory responses.
authors: Department of Microbiology and Immunology and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322; and.
authors: Alexander P R
authors: AP
authors: Bally
authors: Department of Microbiology and Immunology and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322; and.
authors: Peiyuan
authors: P
authors: Lu
authors: Department of Microbiology and Immunology and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322; and Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, China.
authors: Yan
authors: Y
authors: Tang
authors: Department of Microbiology and Immunology and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322; and.
authors: James W
authors: JW
authors: Austin
authors: Department of Microbiology and Immunology and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322; and.
authors: Christopher D
authors: CD
authors: Scharer
authors: Department of Microbiology and Immunology and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322; and.
authors: Rafi
authors: R
authors: Ahmed
authors: Department of Microbiology and Immunology and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322; and jmboss@emory.edu.
authors: Jeremy M
authors: JM
authors: Boss
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D017124:Conserved Sequence; D019175:DNA Methylation; D005786:Gene Expression Regulation; D008024:Ligands; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D059372:Nucleotide Motifs; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D008024:Ligands; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D061026:Programmed Cell Death 1 Receptor; D051193:Toll-Like Receptors