MiR-155 upregulation in dendritic cells is sufficient to break tolerance in vivo by negatively regulating SHIP1

Evan F. Lind, Douglas G. Millar, Dilan Dissanayake, Jonathan C. Savage, Natasha K. Grimshaw, William G. Kerr, Pamela S. Ohashi

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

TLR-induced maturation of dendritic cells (DCs) leads to the production of proinflammatory cytokines as well as the upregulation of various molecules involved in T cell activation. These are believed to be the critical events that account for the induction of the adaptive immune response. In this study, we have examined the role of miR-155 in DC function and the induction of immunity. Using a model in which the transfer of self-Ag-pulsed, TLR-matured DCs can induce a functional CD8 T cell response and autoimmunity, we find that DCs lacking miR-155 have an impaired ability to break immune tolerance. Importantly, transfer of self- Agpulsed DCs overexpressing miR-155 was sufficient to break tolerance in the absence of TLR stimuli. Although these unstimulated DCs induced T cell function in vivo, there was no evidence for the upregulation of costimulatory ligands or cytokine secretion. Further analysis showed that miR-155 influenced the level of the phosphatase SHIP1 in DCs and that the lack of SHIP1 in DCs was sufficient to break T cell tolerance in vivo, again in the absence of TLR-induced DC maturation. Our study demonstrates that the overexpression of miR-155 in DCs is a critical event that is alone sufficient to break self-tolerance and promote a CD8- mediated autoimmune response in vivo. This process is independent of the induction of conventional DC maturation markers, indicating that miR-155 regulation of SHIP represents a unique axis that regulates DC function in vivo.

Original languageEnglish (US)
Pages (from-to)4632-4640
Number of pages9
JournalJournal of Immunology
Volume195
Issue number10
DOIs
StatePublished - Nov 15 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Lind, E. F., Millar, D. G., Dissanayake, D., Savage, J. C., Grimshaw, N. K., Kerr, W. G., & Ohashi, P. S. (2015). MiR-155 upregulation in dendritic cells is sufficient to break tolerance in vivo by negatively regulating SHIP1. Journal of Immunology, 195(10), 4632-4640. https://doi.org/10.4049/jimmunol.1302941