The negative costimulatory molecule PD‐1 modulates the balance between immunity and tolerance via miR‐21

• Published in: European journal of immunology 2011-06, Vol.41 (6), p.1754-1763
• Main Authors: Iliopoulos, Dimitrios, Kavousanaki, Melina, Ioannou, Marianna, Boumpas, Dimitrios, Verginis, Panayotis
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Antigens, Differentiation - genetics; Antigens, Differentiation - metabolism; Apoptosis Regulatory Proteins - immunology; Apoptosis Regulatory Proteins - metabolism; Arthritis, Experimental - chemically induced; Arthritis, Experimental - immunology; Autoimmunity; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - pathology; Cell Growth Processes - drug effects; Cell Growth Processes - genetics; Cells, Cultured; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Gene Expression Regulation - immunology; Interferon-gamma - genetics; Interferon-gamma - metabolism; Interleukin-17 - genetics; Interleukin-17 - metabolism; Kinases; Lymphocytes; Medical research; Mice; Mice, Knockout; MicroRNA; MicroRNAs; MicroRNAs - genetics; MicroRNAs - immunology; MicroRNAs - metabolism; Oligonucleotides, Antisense - pharmacology; Programmed Cell Death 1 Receptor; Programmed death‐1; Protein Binding - genetics; RNA, Small Interfering - genetics; RNA-Binding Proteins - immunology; RNA-Binding Proteins - metabolism; Rodents; Self Tolerance - genetics; STAT5 Transcription Factor - immunology; STAT5 Transcription Factor - metabolism; Tolerance; Transgenes - genetics
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201040646

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.