<i>Mycobacterium tuberculosis</i>promotes Th17 expansion<i>via</i>regulation of human dendritic cells toward a high CD14 and low IL-12p70 phenotype that reprograms upon exogenous IFN-γ

Søndergaard, Jonas Nørskov; Laursen, Janne Marie; Rosholm, Lisbeth Buus; Brix, Susanne

doi:10.1093/intimm/dxu085

Cited by 14 publications

(15 citation statements)

References 59 publications

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“…Previous studies have shown that DCs can mediate Th17 response to M. tuberculosis by signaling through TLR-2, dectin-1, DC-SIGN, and mannose receptors (36, 53, 56). In the present study, we show that monocytes and DCs have differential capacity to modulate Th17 responses to M. tuberculosis and M. tuberculosis -derived antigen fractions.…”

Section: Discussionmentioning

confidence: 99%

IL-1β, But Not Programed Death-1 and Programed Death Ligand Pathway, Is Critical for the Human Th17 Response to Mycobacterium tuberculosis

et al. 2016

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The programed death-1 (PD-1)–programed death ligand-1 (PD-L1) and PD-L2 co-inhibitory pathway has been implicated in the evasion strategies of Mycobacterium tuberculosis. Specifically, M. tuberculosis-induced PD-L1 orchestrates expansion of regulatory T cells and suppression of Th1 response. However, the role of PD pathway in regulating Th17 response to M. tuberculosis has not been investigated. In the present report, we demonstrate that M. tuberculosis and M. tuberculosis-derived antigen fractions have differential abilities to mediate human monocyte- and dendritic cell (DC)-mediated Th17 response and were independent of expression of PD-L1 or PD-L2 on aforementioned antigen-presenting cells. Importantly, we observed that blockade of PD-L1 or PD-1 did not significantly modify either the frequencies of Th17 cells or the production of IL-17 from CD4+ T cells though IFN-γ response was significantly enhanced. On the contrary, IL-1β from monocytes and DCs were critical for the Th17 response to M. tuberculosis. Together, our results indicate that IL-1β, but not members of the programed death pathway, is critical for human Th17 response to M. tuberculosis.

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Section: Discussionmentioning

confidence: 99%

IL-1β, But Not Programed Death-1 and Programed Death Ligand Pathway, Is Critical for the Human Th17 Response to Mycobacterium tuberculosis

et al. 2016

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“…As we have experienced that moDCs from some donors are refractory to IL-12p70 production after LPS stimulation, we co-stimulated moDCs with IFN-c, which allows for a full activation of the Toll-interleukin-1 receptor-domain-containing adaptor-inducing interferonb and nuclear factor-jB responses via the IFN-c receptor even in CD1a-low moDCs. 24,31 LPS + IFN-c-matured moDCs classically attain a pro-inflammatory phenotype with an increased cell-surface expression of maturation and co-stimulatory markers such as HLA-DR, CD80, CD86 and CD40, as well as production of high amounts of IL-12p70, which is needed to promote Th1 polarization. 32 We first screened the potential for helminth PCF, butyrate, TSLP, IL-25 and TSLP + IL-25 in combination to suppress the LPS + IFN-c-induced Type 1 immune profile of high IL-12p70, as low levels of IL-12p70 are a prerequisite for any compound with Th1-PAMP skewing potential that may promote the DCs to develop into a Th2, Th17 or Treg phenotype.…”

Section: Resultsmentioning

confidence: 99%

Body fluid from the parasitic worm Ascaris suum inhibits broad‐acting pro‐inflammatory programs in dendritic cells

et al. 2019

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Dendritic cells (DCs) are essential for generating T-cell-based immune responses through sensing of potential inflammatory and metabolic cues in the local environment. However, there is still limited insight into the processes defining the resultant DC phenotype, including the type of early transcriptional changes in pro-inflammatory cues towards regulatory or type 2 immune-based cues induced by a variety of exogenous and endogenous molecules. Here we compared the ability of a selected number of molecules to modulate the pro-inflammatory phenotype of lipopolysaccharide (LPS) and interferon-c (IFN-c)-stimulated human monocytederived DCs towards an anti-inflammatory or regulatory phenotype, including Ascaris suum body fluid [helminth pseudocoelomic fluid (PCF)], the metabolites succinate and butyrate, and the type 2 cytokines thymic stromal lymphopoietin and interleukin-25. Our data show that helminth PCF and butyrate treatment suppress the T helper type 1 (Th1)inducing pro-inflammatory DC phenotype through induction of different transcriptional programs in DCs. RNA sequencing indicated that helminth PCF treatment strongly inhibited the Th1 and Th17 polarizing ability of LPS + IFN-c-matured DCs by down-regulating myeloid differentiation primary response gene 88 (MyD88)-dependent and MyD88-independent pathways in Toll-like receptor 4 signaling. By contrast, butyrate treatment had a strong Th1-inhibiting action, and transcripts encoding important gut barrier defending factors such as IL18, IL1B and CXCL8 were up-regulated. Collectively, our results further understanding of how compounds from parasites and gut microbiota-derived butyrate may exert immunomodulatory effects on the host immune system.

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“…Remarkably, recent reports have demonstrated that CD14 + monocytes induce Th17 differentiation in response to Candida albicans 37 or in inflammatory arthritis 38 , 39 . In the DC compartment, human DCs that differentiate Th17 cells in mucosal and inflammatory environments express CD14 on their cell surface 40 , 41 , 42 , 43 . Further research has to address whether CD14 expression is also a driving force for Th17 development on the abovementioned monocyte and DC settings.…”

Section: Discussionmentioning

confidence: 99%

“…29 In our human skin experiments, we show that CD14 expression is increased in migrated dermal APCs after IL-1β injection in the skin, stressing that this phenomenon occurs in vivo and providing support for an enhanced expression of CD14 in APCs under proinflammatory conditions. [37][38][39][40][41][42][43][44] However, more work is needed to determine whether the CD14 molecule is de novo upregulated in migrating APCs or there is a preferentially mobilization of CD14 + dermal DCs.…”

Section: Discussionmentioning

confidence: 99%

New roles for CD14 and IL‐β linking inflammatory dendritic cells to IL‐17 production in memory CD4⁺ T cells

et al. 2016

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Interleukin (IL)-1β has proven to be crucial in the differentiation of human and mouse Th17 cells. Although it has become evident that IL-1β has potent IL-17-inducing effects on CD4 + T cells directly, it has not yet been explored whether IL-1β can also prime dendritic cells (DCs) for a Th17 instruction program. Here, we show that human immature DCs exposed to IL-1β promote IL-17 production in human memory CD4 + T cells. IL-1β-primed DCs express high levels of CD14 that mediate IL-17 production through direct interaction with T cells. Moreover, culturing human CD4 + CD45RO + memory T cells with soluble CD14 is sufficient for the upregulation of retinoic acid-related orphan receptor-γ thymus and IL-17 production. In addition, in a human in situ model using tissue-resident skin DCs, upregulation of CD14 expression induced by IL-1β on skin residents DCs promotes IL-17 production in memory T cells; strongly suggesting the in vivo relevance of this mechanism. Our findings uncover new roles for IL-1β and CD14, and may therefore have important consequences for the development of new therapies for Th17-mediated autoimmune diseases and bacterial and fungal pathogenic infections.

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Mycobacterium tuberculosispromotes Th17 expansionviaregulation of human dendritic cells toward a high CD14 and low IL-12p70 phenotype that reprograms upon exogenous IFN-γ

Cited by 14 publications

References 59 publications

IL-1β, But Not Programed Death-1 and Programed Death Ligand Pathway, Is Critical for the Human Th17 Response to Mycobacterium tuberculosis

IL-1β, But Not Programed Death-1 and Programed Death Ligand Pathway, Is Critical for the Human Th17 Response to Mycobacterium tuberculosis

Body fluid from the parasitic worm Ascaris suum inhibits broad‐acting pro‐inflammatory programs in dendritic cells

New roles for CD14 and IL‐β linking inflammatory dendritic cells to IL‐17 production in memory CD4⁺ T cells

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Mycobacterium tuberculosispromotes Th17 expansionviaregulation of human dendritic cells toward a high CD14 and low IL-12p70 phenotype that reprograms upon exogenous IFN-γ

Cited by 14 publications

References 59 publications

IL-1β, But Not Programed Death-1 and Programed Death Ligand Pathway, Is Critical for the Human Th17 Response to Mycobacterium tuberculosis

IL-1β, But Not Programed Death-1 and Programed Death Ligand Pathway, Is Critical for the Human Th17 Response to Mycobacterium tuberculosis

Body fluid from the parasitic worm Ascaris suum inhibits broad‐acting pro‐inflammatory programs in dendritic cells

New roles for CD14 and IL‐β linking inflammatory dendritic cells to IL‐17 production in memory CD4+ T cells

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New roles for CD14 and IL‐β linking inflammatory dendritic cells to IL‐17 production in memory CD4⁺ T cells