On watching the watchers: IDO and type I/II IFN

Puccetti, Paolo

doi:10.1002/eji.200737184

Cited by 69 publications

(69 citation statements)

References 22 publications

(56 reference statements)

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“…In five independent experiments, knockdown of TLR-7 induced 60% ± 16% less IDO expression (P < 0.05, Student t test). Low levels of IFN-γ did not induce IDO expression under these conditions, as reported previously (25). These data indicate that TLR-7-mediated activation of the noncanonical NF-κB pathway is important for IDO expression in human pDCs.…”

Section: Resultssupporting

confidence: 87%

Activation of the noncanonical NF-κB pathway by HIV controls a dendritic cell immunoregulatory phenotype

Manches

Fernandez

Plumas

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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HIV modulates plasmacytoid dendritic cell (pDC) activation via Tolllike receptor 7, inducing type I IFN and inflammatory cytokines. Simultaneously, pDCs up-regulate the expression of indoleamine 2,3 dioxygenase (IDO), which is essential for the induction of regulatory T cells (Tregs), which function to down-modulate immune activation. Here we demonstrate the crucial importance of the noncanonical NF-κB pathway in the establishment of this immunoregulatory phenotype in pDCs. In response to HIV, the noncanonical NF-κB pathway directly induces IDO and involves the recruitment of TNF receptorassociated factor-3 to the Toll-like receptor/MyD88 complex, NF-κB-inducing kinase-dependent IκB kinase-α activation, and p52/RelB nuclear translocation. We also show that pDC-induced Tregs can inhibit conventional DC (cDC) maturation partially through cytotoxic T-lymphocyte antigen (CTLA)-4 engagement. Furthermore, CTLA-4 induces IDO in cDCs in a NF-κB-inducing kinase-dependent way. These CTLA-4-conditioned cDCs can in turn induce Treg differentiation in an IDO-dependent manner. Thus, the noncanonical NF-κB pathway is integral in controlling immunoregulatory phenotypes of both pDCs and cDCs.

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Section: Resultssupporting

confidence: 87%

Activation of the noncanonical NF-κB pathway by HIV controls a dendritic cell immunoregulatory phenotype

Manches

Fernandez

Plumas

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…The most potent mechanism to limit growth of intracellular chlamydiae in human cells is tryptophan depletion upon IFN-γ-induced up-regulation of IDO. Direct immune regulatory functions of IDO and the tryptophan catabolite kynurenine on intracellular chlamydiae are still discussed controversially (17,18). We observed that in hypoxia IDO mRNA and protein expression ( Fig.…”

Section: Resultsmentioning

confidence: 83%

Hypoxia abrogates antichlamydial properties of IFN-γ in human fallopian tube cells in vitro and ex vivo

Roth

König

Zandbergen

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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IFN-γ has an important role in the adaptive immune response against intracellular pathogens. In urogenital tract (UGT) infections with the obligate intracellular pathogen Chlamydia trachomatis, IFN-γ-mediated control of chlamydial growth implies the JAK-STAT signaling cascades and subsequent induction of the indoleamine 2,3-dioxygenase (IDO). As oxygen concentrations in the UGT are low under physiological conditions (O 2 < 5%) and further decrease during an inflammatory process, we wondered whether antibacterial properties of IFN-γ are maintained under hypoxic conditions. Using primary cells that were isolated from human fallopian tubes and an ex vivo human fallopian tube model (HFTM), we found that even high IFN-γ concentrations (200 units/mL) were not sufficient to limit growth of C. trachomatis under hypoxia. Reduced antibacterial activity of IFN-γ under hypoxia was restricted to the urogenital serovars D and L 2 , but was not observed with the ocular serovar A. Impaired effectiveness of IFN-γ on chlamydial growth under hypoxia was accompanied by reduced phosphorylation of Stat-1 on Tyr701 and diminished IDO activity. This study shows that IFN-γ effector functions on intracellular C. trachomatis depend on the environmental oxygen supply, which could explain inadequate bacterial clearance and subsequent chronic infections eventually occurring in the UGT of women.Chlamydia trachomatis | hypoxia | persistence | urogenital tract infections

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“…Sustained IDO induction depends on noncanonical NF-kB activation (19). Because TRIF-mediated signaling may involve noncanonical NF-kB family members (38,39), we hypothesized that a TLR7/TRIF axis could be at work in IDO induction by GpC-ODN.…”

Section: Discussionmentioning

confidence: 99%

“…In most experimental settings of chronic inflammation and autoimmunity, the protective effects of TLR9 ligation are associated with the induction of IDO, an enzyme thatinitiating the suppressive mechanisms of tryptophan depletion and kynurenine production (18)-is operative in both the innate and adaptive forms of immunity (13,19).…”

mentioning

confidence: 99%

A GpC-Rich Oligonucleotide Acts on Plasmacytoid Dendritic Cells To Promote Immune Suppression

Volpi

Fallarino

Bianchi

et al. 2012

The Journal of Immunology

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Short synthetic oligodeoxynucleotides (ODNs) rich in CpG or GpG motifs have been considered as potential modulators of immunity in clinical settings. In this study, we show that a synthetic GpC-ODN conferred highly suppressive activity on mouse splenic plasmacytoid dendritic cells, demonstrable in vivo in a skin test assay. The underlying mechanism involved signaling by noncanonical NF-κB family members and TGF-β–dependent expression of the immunoregulatory enzyme IDO. Unlike CpG-ODNs, the effects of GpC-ODN required TLR7/TRIF-mediated but not TLR9/MyD88-mediated events, as do sensing of viral ssRNA and the drug imiquimod. Induction of IDO by a GpC-containing ODN could also be demonstrated in human dendritic cells, allowing those cells to assist FOXP3+ T cell generation in vitro. Among potentially therapeutic ODNs, this study identifies GpC-rich sequences as novel activators of TLR7-mediated, IDO-dependent regulatory responses.

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On watching the watchers: IDO and type I/II IFN

Cited by 69 publications

References 22 publications

Activation of the noncanonical NF-κB pathway by HIV controls a dendritic cell immunoregulatory phenotype

Activation of the noncanonical NF-κB pathway by HIV controls a dendritic cell immunoregulatory phenotype

Hypoxia abrogates antichlamydial properties of IFN-γ in human fallopian tube cells in vitro and ex vivo

A GpC-Rich Oligonucleotide Acts on Plasmacytoid Dendritic Cells To Promote Immune Suppression

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