Viral dsRNA-activated human dendritic cells produce IL-27, which selectively promotes cytotoxicity in naïve CD8+ T cells

Groot, R de; Beelen, Astrid J. van; Bakdash, Ghaith; Taanman-Kueter, Esther W. M.; Jong, Esther C. de; Kapsenberg, Martien L.

doi:10.1189/jlb.0112045

Cited by 19 publications

(20 citation statements)

References 31 publications

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“…In view of the expression of IL‐27p28 in tolDCs, we investigated IL‐27 production in both DC and tolDC. IL‐27 has been shown to be produced by DCs stimulated with Poly I:C or macrophages stimulated with IFN‐γ + LPS . We did not find any striking effect with Poly I:C in our study but did find that IFN‐γ + LPS induced a strong IL‐27 production in DCs.…”

Section: Discussioncontrasting

confidence: 73%

Human tolerogenic dendritic cells produce IL‐35 in the absence of other IL‐12 family members

et al. 2015

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IL-35 is a cytokine of the IL-12 family, existing as a heterodimer of IL-12p35 and Ebi3. IL-35 has anti-inflammatory properties and is produced by regulatory T cells in humans and mice, where it is required for optimal suppression of immune responses. Distinct from other IL-12 cytokines, the expression of IL-35 has not been described in antigen presenting cells. In view of IL-35 immune-regulatory properties, we investigated the expression, regulation and function of IL-12p35 and Ebi3 in human monocyte derived dendritic cells (moDCs) and tolerogenic DCs (tolDCs). These tolDCs did not produce IL-12p70 or the homodimer IL-12p40. We demonstrate that tolDCs completely lack transcriptional expression of IL-12p40. However, tolDCs maintain mRNA expression of IL-12p35 and Ebi3. Using intracellular flow cytometry and western blot analysis we show that tolDCs produce Ebi3 and IL-12p35, and both can be enhanced upon stimulation with IFN-γ, LPS or CD40L. tolDCs supernatant has the capacity to suppress T-cell activation. Using IL12A silencing we demonstrate that IL-12p35 is required for tolDCs to reach their full suppressive potential. Taken together, our results indicate that tolDCs produce IL-35, providing an additional novel mechanism by which tolDCs elicit their tolerogenic potential.

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Section: Discussioncontrasting

confidence: 73%

Human tolerogenic dendritic cells produce IL‐35 in the absence of other IL‐12 family members

et al. 2015

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“…IFN-γ) in both NK cells and CD8 + effector T cells (37). In addition, IL-27 is also a member of the IL-12 cytokine family, which acts synergistically with IL-12p70 to promote Type-1 responses (34, 42). IL-27 also has a non-redundant role in selectively increasing T cell proliferation and cytotoxicity (34, 42).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, IL-27 is also a member of the IL-12 cytokine family, which acts synergistically with IL-12p70 to promote Type-1 responses (34, 42). IL-27 also has a non-redundant role in selectively increasing T cell proliferation and cytotoxicity (34, 42). However, IL-27 can also exert an inhibitory effect on Th1, Th2, and Th17 cells in pathogen-induced disease models, due to its ability to induce IL-10 production by T cells (43, 44).…”

Section: Discussionmentioning

confidence: 99%

Rapamycin Augments Human DC IL-12p70 and IL-27 Secretion to Promote Allogeneic Type1 Polarization Modulated by NK Cells

Macedo¹,

Turnquist

Castillo-Rama³

et al. 2013

American Journal of Transplantation

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Mammalian target of rapamycin kinase inhibitor (mTORi) rapamycin (RAPA) use in transplantation can lead to inflammatory complications in some patients. Our goal was to better understand how mTORi-exposed human monocyte-derived dendritic cells (DC) stimulated with pro-inflammatory cytokines shape T cell allo-immunity. RAPA-conditioned-DC (RAPA-DC) displayed a more immature phenotype than untreated, control (CTRL)-DC. However, subsequent exposure of RAPA-DC to an inflammatory cytokine cocktail (ICC) plus IFN-γ induced a mature Type-1 promoting phenotype, consisting of elevated HLA-DR and co-stimulatory molecules, augmented IL-12p70 and IL-27 production, but decreased IL-10 secretion compared to CTRL-DC. Co-culture of mature (m) RAPA-DC with allogeneic peripheral blood mononuclear cells resulted in significantly increased Type-1 (IFN-γ) responses by T cells. Moreover, NK cells acted as innate modulators that conveyed activating cell-to-cell contact signals in addition to helper (IFN-γ) and/or regulatory (IL-10) soluble cytokines. We conclude that production of IL12-p70, IL-27, and low IL-10 by RAPA-DC allowed us to elucidate how these cytokines as well as NK-DC interaction shapes T cell allo-immunity. Thus, lack of inhibitory NK cell function during allo-specific T cell activation by human ICC+IFN-γ-stimulated RAPA-DC may represent an unwanted effector mechanism that may underlie RAPA-induced inflammatory events in transplant patients undergoing microbial infection or allograft rejection.

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“…As with IL-12, macrophages and DC can produce IL-23 and IL-27 upon sensing pathogens or their products (56–59). IL-23 is composed by one subunit shared with IL-12 (p40) that is associated with the p19 subunit to constitute the active form of IL-23.…”

Section: Regulation Of Nk Cell Activation and Effector Functions By Imentioning

confidence: 99%

Regulation of NK Cell Activation and Effector Functions by the IL-12 Family of Cytokines: The Case of IL-27

2017

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Natural killer (NK) cells are characterized by their ability to detect and induce apoptosis of susceptible target cells and by secretion of immunoregulatory cytokines such as IFN-γ. Activation of these effector functions is triggered upon recognition of tumor and pathogen (mostly virus)-infected cells and because of a bidirectional cross talk that NK cells establish with other cells of myeloid origin such as dendritic cells (DC) and macrophages. A common characteristic of these myeloid cells is their ability to secrete different members of the IL-12 family of cytokines such as IL-12, IL-23, and IL-27 and cytokines such as IL-15 and IL-18. Although the effect of IL-12, IL-15, and IL-18 has been characterized, the effect of IL-23 and IL-27 on NK cells (especially human) remains ill-defined. Particularly, IL-27 is a cytokine with dual functions as it has been described as pro- and as anti-inflammatory in different experimental settings. Recent evidence indicates that this cytokine indeed promotes human NK cell activation, IFN-γ secretion, NKp46-dependent NK cell-mediated cytotoxicity, and antibody (Ab)-dependent NK cell-mediated cytotoxicity (ADCC) against monoclonal Ab-coated tumor cells. Remarkably, IL-27 also primes NK cells for IL-18 responsiveness, enhancing these functional responses. Consequently, IL-27 acts as a pro-inflammatory cytokine that, in concert with other DC-derived cytokines, hierarchically contributes to NK cells activation and effector functions, which likely contributes to foster the adaptive immune response in different physiopathological conditions.

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Viral dsRNA-activated human dendritic cells produce IL-27, which selectively promotes cytotoxicity in naïve CD8+ T cells

Cited by 19 publications

References 31 publications

Human tolerogenic dendritic cells produce IL‐35 in the absence of other IL‐12 family members

Human tolerogenic dendritic cells produce IL‐35 in the absence of other IL‐12 family members

Rapamycin Augments Human DC IL-12p70 and IL-27 Secretion to Promote Allogeneic Type1 Polarization Modulated by NK Cells

Regulation of NK Cell Activation and Effector Functions by the IL-12 Family of Cytokines: The Case of IL-27

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