Abstract
Dendritic cells (DCs) are key regulators of the adaptive immune response. Tolerogenic
dendritic cells play a crucial role in inducing and maintaining immune tolerance in
autoimmune diseases such as type 1 diabetes in humans as well as in the NOD mouse
model. We previously reported that bone marrow-derived DCs (BM.DCs) from NOD mice, generated with a low dose of GM-CSF (GM/DCs), induce Treg differentiation
and are able to protect NOD mice from diabetes. We had also found that the p38 MAPK/C/EBPβ
axis is involved in regulating the phenotype, as well as the production of IL-10 and
IL-12p70, by tolerogenic GM/DCs. Here, we report that the inhibition of the PI3K signaling
switched the cytokine profile of GM/DCs toward Th17-promoting cytokines without affecting
their phenotype. PI3K inhibition abrogated the production of IL-10 by GM/DCs, whereas
it enhanced their production of IL-23 and TGFβ. Inhibition of PI3K signaling in tolerogenic
GM/DCs also induced naive CD4+ T cells differentiation toward Th17 cells. Mechanistically, PI3K inhibition increased
the DNA-binding activity of C/EBPβ through a GSK3-dependent pathway, which is important
to maintain the semimature phenotype of tolerogenic GM/DCs. Furthermore, analysis
of C/EBPβ−/− GM/DCs demonstrated that C/EBPβ is required for IL-23 production. Of physiological
relevance, the level of protection from diabetes following transfusion of GM/DCs into
young NOD mice was significantly reduced when NOD mice were transfused with GM/DCs
pretreated with a PI3K inhibitor. Our data suggest that PI3K/C/EBPβ signaling is important
in controlling tolerogenic function of GM/DCs by limiting their Th17-promoting cytokines.
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Article Info
Publication History
Published online: November 14, 2022
Accepted:
November 8,
2022
Received in revised form:
November 1,
2022
Received:
April 14,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Elsevier Inc. All rights reserved.
