title: The negative costimulatory molecule PD-1 modulates the balance between immunity and tolerance via miR-21.
abstract: Disruption of the programmed death-1 (PD-1) pathway leads to breakdown of peripheral tolerance and initiation of autoimmunity. The molecular pathways that mediate this effect remain largely unknown. We report here that PD-1 knockout (PD-1(-/-) ) mice develop more severe and sustained Ag-induced arthritis (AIA) than WT animals, which is associated with increased T-cell proliferation and elevated levels of IFN-γ and IL-17 secretion. MicroRNA analysis of Ag-specific CD4(+) T cells revealed a significant upregulation of microRNA 21 (miR-21) in PD-1(-/-) T cells compared with WT controls. In addition, PD-1 inhibition, via siRNA, upregulated miR-21 expression and enhanced STAT5 binding in the miR-21 promoter area. Computational analysis confirmed that miR-21 targets directly the expression of programmed cell death 4 (PDCD4) and overexpression of miR-21 in cells harboring the 3'UTR of PDCD4 resulted in reduced transcription and PDCD4 protein expression. Importantly, in vitro delivery of antisense-miR-21 suppressed the Ag-specific proliferation and cytokine secretion by PD-1(-/-) T cells, whereas adoptive transfer of Ag-specific T cells, overexpressing miR-21, induced severe AIA. Collectively, our data demonstrate that breakdown of tolerance in PD-1(-/-) mice activates a signaling cascade mediated by STAT5, miR-21, and PDCD4 and establish their role in maintaining the balance between immune activation and tolerance.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. dimittrios_iliopoulos@dfci.harvard.edu
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Iliopoulos
authors.forename: Melina
authors.initials: M
authors.lastname: Kavousanaki
authors.forename: Marianna
authors.initials: M
authors.lastname: Ioannou
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Boumpas
authors.forename: Panayotis
authors.initials: P
authors.lastname: Verginis
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D061026:Programmed Cell Death 1 Receptor; D011485:Protein Binding / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000276:immunology / Q000378:metabolism; D017634:Self Tolerance / Q000235:genetics; D019076:Transgenes / Q000235:genetics
chemical_list: D000943:Antigens, Differentiation; D051017:Apoptosis Regulatory Proteins; D020381:Interleukin-17; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; C491383:Pdcd1 protein, mouse; C498443:Pdcd4 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D050799:STAT5 Transcription Factor; D007371:Interferon-gamma