Induction of Peripheral Tolerance in Ongoing Autoimmune Inflammation Requires Interleukin 27 Signaling in Dendritic Cells

Thomé, Rodolfo; Moore, Jason N.; Mari, Elisabeth R.; Rasouli, Javad; Hwang, Daniel; Yoshimura, Satoshi; Ćirić, Bogoljub; Zhang, Guang‐Xian; Rostami, Abdolmohamad

doi:10.3389/fimmu.2017.01392

Cited by 21 publications

(35 citation statements)

References 54 publications

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“…Tsoumarkidou et al also found that tolerogenic CD1c + DCs regulate development of T regs via IL-27/IL-10 inducible co-stimulatory ligands ( 27 ). Rostami et al have published data showing that the induction of peripheral tolerance is dependent on IL-27-mediated signal transduction pathway in DCs ( 28 ). These data suggest that regulatory mechanisms of IL-27 in the immune system are extremely complex and that IL-27 may play a dual role in equilibrium between autoimmunity and immune tolerance.…”

Section: Discussionmentioning

confidence: 99%

Distinct Role of IL-27 in Immature and LPS-Induced Mature Dendritic Cell-Mediated Development of CD4+ CD127+3G11+ Regulatory T Cell Subset

2018

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Interleukin-27 (IL-27) plays an important role in regulation of anti-inflammatory responses and autoimmunity; however, the molecular mechanisms of IL-27 in modulation of immune tolerance and autoimmunity have not been fully elucidated. Dendritic cells (DCs) play a central role in regulating immune responses mediated by innate and adaptive immune systems, but regulatory mechanisms of DCs in CD4+ T cell-mediated immune responses have not yet been elucidated. Here we show that IL-27 treated mature DCs induced by LPS inhibit immune tolerance mediated by LPS-stimulated DCs. IL-27 treatment facilitates development of the CD4+ CD127+3G11+ regulatory T cell subset in vitro and in vivo. By contrast, IL-27 treated immature DCs fail to modulate development of the CD4+CD127+3G11+ regulatory T cell sub-population in vitro and in vivo. Our results suggest that IL-27 may break immune tolerance induced by LPS-stimulated mature DCs through modulating development of a specific CD4+ regulatory T cell subset mediated by 3G11 and CD127. Our data reveal a new cellular regulatory mechanism of IL-27 that targets DC-mediated immune responses in autoimmune diseases such as multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE).

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Section: Discussionmentioning

confidence: 99%

Distinct Role of IL-27 in Immature and LPS-Induced Mature Dendritic Cell-Mediated Development of CD4+ CD127+3G11+ Regulatory T Cell Subset

2018

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“…STAT1 −/− , STAT3 −/− , and WT BMDCs were generated according to a previously described protocol (3). Briefly, BM cells were seeded at 2 × 10 6 cells/mL in Petri dish in complete IMDM supplemented with 100 ng/mL of recombinant mouse Flt-3 (R&D Systems, Minneapolis, MN, USA).…”

Section: Generation Of Bmdcsmentioning

confidence: 99%

“…We and others have reported that i.v. delivery of auto-Ag in mice with EAE induces expression of PD-L1 by APCs (2,3). Given the importance of PD-1 and its ligands in immune tolerance, we investigated their role in i.v.…”

Section: Intravenous Tolerance Induction In Experimental Autoimmune Ementioning

confidence: 99%

“…Even though certain key players in i.v. tolerance induction, such as interleukin (IL)-10, IL-27, and programmed death ligand 1 (PD-L1), have been identified (2,3), its complete mechanisms have not been elucidated. This lack of specific knowledge also includes the cell types involved, sequence of their interactions, and relative relevance of the periphery vs. the central nervous system (CNS) in tolerance induction and maintenance over time.…”

Section: Introductionmentioning

confidence: 99%

“…tolerance in EAE (3); in particular, IL-27 signaling in DCs was required for tolerance induction, whereas its signaling in T cells was not. IL-27-dependent tolerance induction relied on cooperation of distinct subsets of spleen DCs with the ability to induce T cell-derived IL-10 and interferon-gamma (IFN-γ) (3).…”

Section: Introductionmentioning

confidence: 99%

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Interferon-γ/Interleukin-27 Axis Induces Programmed Death Ligand 1 Expression in Monocyte-Derived Dendritic Cells and Restores Immune Tolerance in Central Nervous System Autoimmunity

et al. 2020

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Antigen (Ag)-specific tolerance induction by intravenous (i. v.) injection of high-dose auto-Ags has been explored for therapy of autoimmune diseases, including multiple sclerosis (MS). It is thought that the advantage of such Ag-specific therapy over non-specific immunomodulatory treatments would be selective suppression of a pathogenic immune response without impairing systemic immunity, thus avoiding adverse effects of immunosuppression. Auto-Ag i.v. tolerance induction has been extensively studied in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and limited clinical trials demonstrated that it is safe and beneficial to a subset of MS patients. Nonetheless, the mechanisms of i.v. tolerance induction are incompletely understood, hampering the development of better approaches and their clinical application. Here, we describe a pathway whereby auto-Ag i.v. injected into mice with ongoing clinical EAE induces interferon-gamma (IFN-γ) secretion by auto-Ag-specific CD4 + T cells, triggering interleukin (IL)-27 production by conventional dendritic cells type 1 (cDC1). IL-27 then, via signal transducer and activator of transcription 3 activation, induces programmed death ligand 1 (PD-L1) expression by monocyte-derived dendritic cells (moDCs) in the central nervous system of mice with EAE. PD-L1 interaction with programmed cell death protein 1 on pathogenic CD4 + T cells leads to their apoptosis/anergy, resulting in disease amelioration. These findings identify a key role of the IFN-γ/IL-27/PD-L1 axis, involving T cells/cDC1/moDCs in the induction of i.v. tolerance.

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Chloroquine‐treated dendritic cells require STAT1 signaling for their tolerogenic activity

et al. 2018

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MS and EAE are T cell-driven autoimmune diseases of the CNS where IL-17-producing Th17 cells promote damage and are pathogenic. Conversely, tolerogenic DCs induce Treg cells and suppress Th17 cells. Chloroquine (CQ) suppresses EAE through the modulation of DCs by unknown mechanisms. Here, we show that STAT 1 is necessary for CQ-induced tolerogenic DCs (tolDCs) to efficiently suppress EAE. We observed that CQ induces phosphorylation of STAT1 in DCs in vivo and in vitro. Genetic blockage of STAT1 abrogated the suppressive activity of CQ-treated DCs. Opposed to its WT counterparts, CQ-treated STAT1 BMDCs were unable to suppress Th17 cells and increased EAE severity. Our findings show that STAT1 is a major signaling pathway in CQ-induced tolDCs and may shed light on new therapeutic avenues for the induction of tolDCs in autoimmune diseases such as MS.

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Induction of Peripheral Tolerance in Ongoing Autoimmune Inflammation Requires Interleukin 27 Signaling in Dendritic Cells

Cited by 21 publications

References 54 publications

Distinct Role of IL-27 in Immature and LPS-Induced Mature Dendritic Cell-Mediated Development of CD4+ CD127+3G11+ Regulatory T Cell Subset

Distinct Role of IL-27 in Immature and LPS-Induced Mature Dendritic Cell-Mediated Development of CD4+ CD127+3G11+ Regulatory T Cell Subset

Interferon-γ/Interleukin-27 Axis Induces Programmed Death Ligand 1 Expression in Monocyte-Derived Dendritic Cells and Restores Immune Tolerance in Central Nervous System Autoimmunity

Chloroquine‐treated dendritic cells require STAT1 signaling for their tolerogenic activity

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