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


Journal of Clinical & Cellular Immunology

Author(s): Iliopoulos D, Kavousanaki M, Ioannou M, Boumpas D, Verginis P

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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. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. This article was published in Eur J Immunol and referenced in Journal of Clinical & Cellular Immunology

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