miR-155 Upregulation in Dendritic Cells Is Sufficient To Break Tolerance In Vivo by Negatively Regulating SHIP1

• Published in: The Journal of immunology (1950) 2015-11, Vol.195 (10), p.4632-4640
• Main Authors: Lind, Evan F, Millar, Douglas G, Dissanayake, Dilan, Savage, Jonathan C, Grimshaw, Natasha K, Kerr, William G, Ohashi, Pamela S
• Format: Article
• Language: English
• Subjects: Animals; Autoimmunity - genetics; Autoimmunity - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Differentiation - immunology; Cells, Cultured; Dendritic Cells - cytology; Dendritic Cells - metabolism; Immune Tolerance - genetics; Immune Tolerance - immunology; Inositol Polyphosphate 5-Phosphatases; Lymphocyte Activation - immunology; Mice; Mice, Inbred C57BL; Mice, Transgenic; MicroRNAs - biosynthesis; MicroRNAs - genetics; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - metabolism; Up-Regulation
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1302941

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- Ag-pulsed 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.