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 language | English (US) |
|---|---|
| Pages (from-to) | 4632-4640 |
| Number of pages | 9 |
| Journal | Journal of Immunology |
| Volume | 195 |
| Issue number | 10 |
| DOIs | |
| State | Published - Nov 15 2015 |
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ASJC Scopus subject areas
- Immunology
Cite this
MiR-155 upregulation in dendritic cells is sufficient to break tolerance in vivo by negatively regulating SHIP1. / Lind, Evan; Millar, Douglas G.; Dissanayake, Dilan; Savage, Jonathan C.; Grimshaw, Natasha K.; Kerr, William G.; Ohashi, Pamela S.
In: Journal of Immunology, Vol. 195, No. 10, 15.11.2015, p. 4632-4640.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - MiR-155 upregulation in dendritic cells is sufficient to break tolerance in vivo by negatively regulating SHIP1
AU - Lind, Evan
AU - Millar, Douglas G.
AU - Dissanayake, Dilan
AU - Savage, Jonathan C.
AU - Grimshaw, Natasha K.
AU - Kerr, William G.
AU - Ohashi, Pamela S.
PY - 2015/11/15
Y1 - 2015/11/15
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.1302941
DO - 10.4049/jimmunol.1302941
M3 - Article
VL - 195
SP - 4632
EP - 4640
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 10
ER -