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HHV-6B induces IFN-lambda1 responses in cord plasmacytoid dendritic cells through TLR9.

Nordström I, Eriksson K - PLoS ONE (2012)

Bottom Line: Similarly, blockage of TLR9 counteracted HHV-6Bs effects on the Th1/Th2 balance.The lack of effect of IFN-lambda1 correlated with the absence of the IFN-lambda receptor IL-28Ralfa chain on the cell surface of both resting and activated CD4+ T-cells.However, human CD4+ T-cells do not express the IFN-lambda receptor and are refractory to IFN-lambda1 treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

ABSTRACT
Human herpesvirus type 6B (HHV-6B) is a strong inducer of IFN-alpha and has the capacity to promote Th1 responses and block Th2 responses in vitro. In this study we addressed whether inactivated HHV-6B can also induce IFN lambda responses and to what extent interferons alpha and lambda affect Th1/Th2 polarization. We show that inactivated HHV-6B induced IFN-lambda1 (IL-29) but not IFN-lambda2 (IL-28A) responses in plasmacytoid DC and that this induction was mediated through TLR9. We have previously shown that HHV-6B promotes Th1 responses and blocks Th2 responses in both humans and mice. We now show that neutralization of IFN-alpha but not IFN-lambda1 blocked the HHV-6B-induced enhancement of Th1 responses in MLR, but did not affect the HHV-6-induced dampening of Th2 responses. Similarly, blockage of TLR9 counteracted HHV-6Bs effects on the Th1/Th2 balance. In addition, IFN-alpha but not IFN-lambda1 promoted IFN-gamma production and blocked IL-5 and IL-13 production in purified CD4+ T-cells. The lack of effect of IFN-lambda1 correlated with the absence of the IFN-lambda receptor IL-28Ralfa chain on the cell surface of both resting and activated CD4+ T-cells. We conclude that inactivated HHV-6B is a strong inducer of IFN-lambda1 in plasmacytoid DC and that this induction is TLR9-dependent. However, human CD4+ T-cells do not express the IFN-lambda receptor and are refractory to IFN-lambda1 treatment. The HHV-6B-induced alterations in the Th1/Th2 balance are instead mediated mainly through TLR9 and IFN-alpha.

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IFN-alpha but not IFN-lambda1 promote Th1 responses and block Th2 responses in activated cord CD4+ T-cells.Cord blood CD4+ T-cells were activated with anti-CD3 (A–B) or anti-CD3 and anti-CD28 (C) in the presence or absence of recombinant human IFN-alpha or IFN-lambda1. Supernatants were collected after 48 h and analyzed for IFN-gamma (A), IL-5 (B) and IL-13 (C) content. Data are expressed as medians and the 25% and 75% percentile (the boxes) with the minimum and maximum responses for n = 5. *  =  p<0.05 using ANOVA with Bonferroni's multiple comparison test.
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pone-0038683-g004: IFN-alpha but not IFN-lambda1 promote Th1 responses and block Th2 responses in activated cord CD4+ T-cells.Cord blood CD4+ T-cells were activated with anti-CD3 (A–B) or anti-CD3 and anti-CD28 (C) in the presence or absence of recombinant human IFN-alpha or IFN-lambda1. Supernatants were collected after 48 h and analyzed for IFN-gamma (A), IL-5 (B) and IL-13 (C) content. Data are expressed as medians and the 25% and 75% percentile (the boxes) with the minimum and maximum responses for n = 5. *  =  p<0.05 using ANOVA with Bonferroni's multiple comparison test.

Mentions: To assess whether IFN-lambda1 shares the CD4+ T-cell immune-modulatory functions of IFN-alpha, we added recombinant human IFN-alpha and IFN-lambda1 to cultures of anti-CD3-stimulated cord CD4+ T-cells and measured their production of IFN-gamma, IL-5 and IL-13. To ascertain that the recombinant cytokines used were biologically functional we first assessed their ability to induce MxA transcription in purified pDC and found that four hour incubation with IFN-alpha or IFN-lambda1 enhanced the MxA transcription 50-fold and 10-fold, respectively. Since anti-CD3 activation alone did not give rise to any measurable IL-13 responses (not shown), we added soluble anti-CD28 to these cultures. As expected, IFN-alpha had profound effects on the cytokine production profiles and promoted both IFN-gamma and IL-10 responses and blocked IL-5 and IL-13 responses by the T-cells (Fig. 4). IFN-lambda1 on the other hand did not affect the production of any of these cytokines (Fig. 4).


HHV-6B induces IFN-lambda1 responses in cord plasmacytoid dendritic cells through TLR9.

Nordström I, Eriksson K - PLoS ONE (2012)

IFN-alpha but not IFN-lambda1 promote Th1 responses and block Th2 responses in activated cord CD4+ T-cells.Cord blood CD4+ T-cells were activated with anti-CD3 (A–B) or anti-CD3 and anti-CD28 (C) in the presence or absence of recombinant human IFN-alpha or IFN-lambda1. Supernatants were collected after 48 h and analyzed for IFN-gamma (A), IL-5 (B) and IL-13 (C) content. Data are expressed as medians and the 25% and 75% percentile (the boxes) with the minimum and maximum responses for n = 5. *  =  p<0.05 using ANOVA with Bonferroni's multiple comparison test.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368904&req=5

pone-0038683-g004: IFN-alpha but not IFN-lambda1 promote Th1 responses and block Th2 responses in activated cord CD4+ T-cells.Cord blood CD4+ T-cells were activated with anti-CD3 (A–B) or anti-CD3 and anti-CD28 (C) in the presence or absence of recombinant human IFN-alpha or IFN-lambda1. Supernatants were collected after 48 h and analyzed for IFN-gamma (A), IL-5 (B) and IL-13 (C) content. Data are expressed as medians and the 25% and 75% percentile (the boxes) with the minimum and maximum responses for n = 5. *  =  p<0.05 using ANOVA with Bonferroni's multiple comparison test.
Mentions: To assess whether IFN-lambda1 shares the CD4+ T-cell immune-modulatory functions of IFN-alpha, we added recombinant human IFN-alpha and IFN-lambda1 to cultures of anti-CD3-stimulated cord CD4+ T-cells and measured their production of IFN-gamma, IL-5 and IL-13. To ascertain that the recombinant cytokines used were biologically functional we first assessed their ability to induce MxA transcription in purified pDC and found that four hour incubation with IFN-alpha or IFN-lambda1 enhanced the MxA transcription 50-fold and 10-fold, respectively. Since anti-CD3 activation alone did not give rise to any measurable IL-13 responses (not shown), we added soluble anti-CD28 to these cultures. As expected, IFN-alpha had profound effects on the cytokine production profiles and promoted both IFN-gamma and IL-10 responses and blocked IL-5 and IL-13 responses by the T-cells (Fig. 4). IFN-lambda1 on the other hand did not affect the production of any of these cytokines (Fig. 4).

Bottom Line: Similarly, blockage of TLR9 counteracted HHV-6Bs effects on the Th1/Th2 balance.The lack of effect of IFN-lambda1 correlated with the absence of the IFN-lambda receptor IL-28Ralfa chain on the cell surface of both resting and activated CD4+ T-cells.However, human CD4+ T-cells do not express the IFN-lambda receptor and are refractory to IFN-lambda1 treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

ABSTRACT
Human herpesvirus type 6B (HHV-6B) is a strong inducer of IFN-alpha and has the capacity to promote Th1 responses and block Th2 responses in vitro. In this study we addressed whether inactivated HHV-6B can also induce IFN lambda responses and to what extent interferons alpha and lambda affect Th1/Th2 polarization. We show that inactivated HHV-6B induced IFN-lambda1 (IL-29) but not IFN-lambda2 (IL-28A) responses in plasmacytoid DC and that this induction was mediated through TLR9. We have previously shown that HHV-6B promotes Th1 responses and blocks Th2 responses in both humans and mice. We now show that neutralization of IFN-alpha but not IFN-lambda1 blocked the HHV-6B-induced enhancement of Th1 responses in MLR, but did not affect the HHV-6-induced dampening of Th2 responses. Similarly, blockage of TLR9 counteracted HHV-6Bs effects on the Th1/Th2 balance. In addition, IFN-alpha but not IFN-lambda1 promoted IFN-gamma production and blocked IL-5 and IL-13 production in purified CD4+ T-cells. The lack of effect of IFN-lambda1 correlated with the absence of the IFN-lambda receptor IL-28Ralfa chain on the cell surface of both resting and activated CD4+ T-cells. We conclude that inactivated HHV-6B is a strong inducer of IFN-lambda1 in plasmacytoid DC and that this induction is TLR9-dependent. However, human CD4+ T-cells do not express the IFN-lambda receptor and are refractory to IFN-lambda1 treatment. The HHV-6B-induced alterations in the Th1/Th2 balance are instead mediated mainly through TLR9 and IFN-alpha.

Show MeSH
Related in: MedlinePlus