Abstract
Tolerogenic dendritic cells (toDCs) are crucial to controlling the development of autoreactive T cell responses and the prevention of autoimmunity. We have reported that NOD.CD11cStat5b-CA transgenic mice expressing a constitutively active (CA) form of Stat5b under the control of a CD11c promoter are protected from diabetes and that Stat5b-CA-expressing DCs are tolerogenic and halt ongoing diabetes in NOD mice. However, the molecular mechanisms by which Stat5b-CA modulates DC tolerogenic function are not fully understood. Here, we used bone marrow-derived DCs (BMDCs) from NOD.CD11cStat5b-CA transgenic mice (Stat5b-CA.BMDCs) and found that Stat5b-CA.BMDCs displayed high levels of MHC class II, CD80, CD86, PD-L1, and PD-L2 and produced elevated amounts of TGFβ but low amounts of TNFα and IL-23. Stat5b-CA.BMDCs upregulated Irf4 and downregulated Irf8 genes and protein expression and promoted CD11c+CD11b+ DC2 subset differentiation. Interestingly, we found that the histone methyltransferase Ezh2 and Stat5b-CA bound gamma-interferon activated site (GAS) sequences in the Irf8 enhancer IRF8 transcription, whereas Stat5b but not Ezh2 bound GAS sequences in the Irf4 promoter to enhance IRF4 transcription. Injection of Stat5b-CA.BMDCs into prediabetic NOD mice halted progression of islet inflammation and protected against diabetes. Importantly, inhibition of Ezh2 in tolerogenic Stat5b-CA.BMDCs reduced their ability to prevent diabetes development in NOD recipient mice. Taken together, our data suggest that the active form of Stat5b induces tolerogenic DC function by modulating IRF4 and IRF8 expression through recruitment of Ezh2 and highlight the fundamental role of Ezh2 in Stat5b-mediated induction of tolerogenic DC function.
Highlights
Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that are essential for the induction of effective immunity and the maintenance of immune tolerance
Sci. 2020, 21, 6453 the molecular mechanisms underlying mature DC tolerogenic function, we used in vitro bone marrow-derived DCs (BMDCs) generated by a combination of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and IL-4, a condition that induces the generation of conventional DCs
To overcome the Stat5 defect in DCs of diabetes-prone NOD mice, we generated transgenic mice (NOD.CD11cStat5b-CA) expressing a DC-specific, constitutively active form of the Stat5b gene. This transgenic model allowed us to define the critical role of Stat5b as a transcription factor in reprogramming immunogenic to tolerogenic DCs [9]. in the present study, we investigated the molecular mechanisms by which active Stat5b induced tolerogenic DC function
Summary
Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that are essential for the induction of effective immunity and the maintenance of immune tolerance. Some danger-associated molecular patterns and immunosuppressive cytokines have been shown to drive the maturation of DCs that possess tolerogenic properties [3,4] These fully mature tolerogenic DCs (toDCs), along with expression of co-stimulatory molecules, express co-inhibitory molecules such as programmed death ligands PD-L1 and PD-L2 and immunoglobulin-like transcript 3 (ILT3). Treg differentiation induced by toDCs has been shown to be mediated through membrane-bound PD-L1, which blocks the Akt/mTOR pathway to preferentially promote naive T cells to become Tregs [7] Secreted cytokines such as IL-10, IL-27, and TGF-β, as well as retinoic acid and IDO, have been shown to be able to convert naive CD4+ T cells into Tregs
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