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Interferon-α-conditioned human monocytes combine a Th1-orienting attitude with the induction of autologous Th17 responses: role of IL-23 and IL-12.

Santini SM, Lapenta C, Donati S, Spadaro F, Belardelli F, Ferrantini M - PLoS ONE (2011)

Bottom Line: Priming of naïve CD4 T cells with autologous IFN-DC in the presence of either SEA or anti-CD3, resulted, in addition to a prominent expansion of CXCR3+ IFN-γ-producing CD4 Th1 cells, in the emergence of two distinct subsets of IL-17-producing CD4 T cells: i) a predominant Th17 population selectively producing IL-17 and expressing CCR6; ii) a minor Th1/Th17 population, producing both IL-17 and IFN-γ.After phagocytosis of apoptotic cells, IFN-DC induced Th17 cell expansion and IL-17 release.Notably, the use of neutralizing antibodies revealed that IL-23 was an essential cytokine in mediating Th17 cell development by IFN-DC.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.

ABSTRACT
IFN-α exerts multiple effects leading to immune protection against pathogens and cancer as well to autoimmune reactions by acting on monocytes and dendritic cells. We analyzed the versatility of human monocytes conditioned by IFN-α towards dendritic cell differentiation (IFN-DC) in shaping the autologous T-helper response. Priming of naïve CD4 T cells with autologous IFN-DC in the presence of either SEA or anti-CD3, resulted, in addition to a prominent expansion of CXCR3+ IFN-γ-producing CD4 Th1 cells, in the emergence of two distinct subsets of IL-17-producing CD4 T cells: i) a predominant Th17 population selectively producing IL-17 and expressing CCR6; ii) a minor Th1/Th17 population, producing both IL-17 and IFN-γ. After phagocytosis of apoptotic cells, IFN-DC induced Th17 cell expansion and IL-17 release. Notably, the use of neutralizing antibodies revealed that IL-23 was an essential cytokine in mediating Th17 cell development by IFN-DC. The demonstration of the IFN-DC-induced expansion of both Th1 and Th17 cell populations reveals the intrinsic plasticity of these DC in orienting the immune response and provides a mechanistic link between IFN-α and the onset of autoimmune phenomena, which have been correlated with both IL-17 production and exposure to IFN-α.

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Related in: MedlinePlus

Release of IL-6 and IL-1β after co-culture of naïve CD4 T cells with autologous DC.The amount of IL-6 and IL-1β released in the co-cultures of naïve CD4 T cells with autologous DC, with or without activation with SEA or anti-CD3 coated beads, was determined by ELISA after 6 days of co-culture. The values represent the mean +/− SD of four independent experiments. Statistical analysis was performed by Mann-Whitney test. * p<0.05.
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pone-0017364-g003: Release of IL-6 and IL-1β after co-culture of naïve CD4 T cells with autologous DC.The amount of IL-6 and IL-1β released in the co-cultures of naïve CD4 T cells with autologous DC, with or without activation with SEA or anti-CD3 coated beads, was determined by ELISA after 6 days of co-culture. The values represent the mean +/− SD of four independent experiments. Statistical analysis was performed by Mann-Whitney test. * p<0.05.

Mentions: Notably, the profile of IFN-DC cytokine production was strongly suggestive of a Th17 phenotype-promoting milieu (Fig. 1A), as IL-1β, IL-6, and TNF-α, together with IL-23, have been found to induce and sustain Th17 development [12], [13]. In the light of the particular efficiency of IFN-DC in inducing high levels of CD154 in CD4 T cells (Fig. 2A and B) that are known to reciprocally activate DC through CD40-CD154 interaction, we then analyzed the cytokine production during the co-culture of naïve CD4 T cells with autologous DC in the absence or in the presence of either SEA or anti-CD3 coated beads, especially focusing on IL-6 and IL-1β, which are known to play a key role in Th17 development [13]. As shown in Fig. 3, considerable levels of IL-6 (upper panel) and IL-1β (lower panel) were found in the co-cultures of IFN-DC with naïve CD4 T cells in the absence of any stimulus, and a similar increase was induced upon stimulation with SEA or anti-CD3. In contrast, very low levels of IL-6 were secreted in the co-cultures of IL-4-DC with naïve CD4 T cells in the absence of stimuli, where IL-1β was virtually undetectable. An increase of IL-6 secretion in the co-cultures of naïve CD4 T cells with IL-4-DC occurred substantially in the presence of SEA and, at a lower extent, of anti-CD3, whereas IL-1β secretion was revealed only upon stimulation with SEA. Large amounts of TNF-α, ranging from 1,159 pg +/− 306 to 1,592 +/− 254 (mean +/− SD values), were invariably present in all culture conditions and with both types of DC, while TGF-β was in any case undetectable (data not shown).


Interferon-α-conditioned human monocytes combine a Th1-orienting attitude with the induction of autologous Th17 responses: role of IL-23 and IL-12.

Santini SM, Lapenta C, Donati S, Spadaro F, Belardelli F, Ferrantini M - PLoS ONE (2011)

Release of IL-6 and IL-1β after co-culture of naïve CD4 T cells with autologous DC.The amount of IL-6 and IL-1β released in the co-cultures of naïve CD4 T cells with autologous DC, with or without activation with SEA or anti-CD3 coated beads, was determined by ELISA after 6 days of co-culture. The values represent the mean +/− SD of four independent experiments. Statistical analysis was performed by Mann-Whitney test. * p<0.05.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3046151&req=5

pone-0017364-g003: Release of IL-6 and IL-1β after co-culture of naïve CD4 T cells with autologous DC.The amount of IL-6 and IL-1β released in the co-cultures of naïve CD4 T cells with autologous DC, with or without activation with SEA or anti-CD3 coated beads, was determined by ELISA after 6 days of co-culture. The values represent the mean +/− SD of four independent experiments. Statistical analysis was performed by Mann-Whitney test. * p<0.05.
Mentions: Notably, the profile of IFN-DC cytokine production was strongly suggestive of a Th17 phenotype-promoting milieu (Fig. 1A), as IL-1β, IL-6, and TNF-α, together with IL-23, have been found to induce and sustain Th17 development [12], [13]. In the light of the particular efficiency of IFN-DC in inducing high levels of CD154 in CD4 T cells (Fig. 2A and B) that are known to reciprocally activate DC through CD40-CD154 interaction, we then analyzed the cytokine production during the co-culture of naïve CD4 T cells with autologous DC in the absence or in the presence of either SEA or anti-CD3 coated beads, especially focusing on IL-6 and IL-1β, which are known to play a key role in Th17 development [13]. As shown in Fig. 3, considerable levels of IL-6 (upper panel) and IL-1β (lower panel) were found in the co-cultures of IFN-DC with naïve CD4 T cells in the absence of any stimulus, and a similar increase was induced upon stimulation with SEA or anti-CD3. In contrast, very low levels of IL-6 were secreted in the co-cultures of IL-4-DC with naïve CD4 T cells in the absence of stimuli, where IL-1β was virtually undetectable. An increase of IL-6 secretion in the co-cultures of naïve CD4 T cells with IL-4-DC occurred substantially in the presence of SEA and, at a lower extent, of anti-CD3, whereas IL-1β secretion was revealed only upon stimulation with SEA. Large amounts of TNF-α, ranging from 1,159 pg +/− 306 to 1,592 +/− 254 (mean +/− SD values), were invariably present in all culture conditions and with both types of DC, while TGF-β was in any case undetectable (data not shown).

Bottom Line: Priming of naïve CD4 T cells with autologous IFN-DC in the presence of either SEA or anti-CD3, resulted, in addition to a prominent expansion of CXCR3+ IFN-γ-producing CD4 Th1 cells, in the emergence of two distinct subsets of IL-17-producing CD4 T cells: i) a predominant Th17 population selectively producing IL-17 and expressing CCR6; ii) a minor Th1/Th17 population, producing both IL-17 and IFN-γ.After phagocytosis of apoptotic cells, IFN-DC induced Th17 cell expansion and IL-17 release.Notably, the use of neutralizing antibodies revealed that IL-23 was an essential cytokine in mediating Th17 cell development by IFN-DC.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.

ABSTRACT
IFN-α exerts multiple effects leading to immune protection against pathogens and cancer as well to autoimmune reactions by acting on monocytes and dendritic cells. We analyzed the versatility of human monocytes conditioned by IFN-α towards dendritic cell differentiation (IFN-DC) in shaping the autologous T-helper response. Priming of naïve CD4 T cells with autologous IFN-DC in the presence of either SEA or anti-CD3, resulted, in addition to a prominent expansion of CXCR3+ IFN-γ-producing CD4 Th1 cells, in the emergence of two distinct subsets of IL-17-producing CD4 T cells: i) a predominant Th17 population selectively producing IL-17 and expressing CCR6; ii) a minor Th1/Th17 population, producing both IL-17 and IFN-γ. After phagocytosis of apoptotic cells, IFN-DC induced Th17 cell expansion and IL-17 release. Notably, the use of neutralizing antibodies revealed that IL-23 was an essential cytokine in mediating Th17 cell development by IFN-DC. The demonstration of the IFN-DC-induced expansion of both Th1 and Th17 cell populations reveals the intrinsic plasticity of these DC in orienting the immune response and provides a mechanistic link between IFN-α and the onset of autoimmune phenomena, which have been correlated with both IL-17 production and exposure to IFN-α.

Show MeSH
Related in: MedlinePlus