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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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CD4+ T-cells do not express IL-28Ralpha.Resting or activated cord blood mononuclear cells were analyzed for IL-28Ralpha expression using FACS. IL-28Ralpha expression (histograms) on pDC (A) or CD4+ T-cells obtained directly upon isolation (B) or after 24 h incubation with anti-CD3 (C) or recombinant human IFN-alpha (D). Filled red areas represent isotype-PE control and blue lines represent IL-28Ralpha-PE.
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pone-0038683-g005: CD4+ T-cells do not express IL-28Ralpha.Resting or activated cord blood mononuclear cells were analyzed for IL-28Ralpha expression using FACS. IL-28Ralpha expression (histograms) on pDC (A) or CD4+ T-cells obtained directly upon isolation (B) or after 24 h incubation with anti-CD3 (C) or recombinant human IFN-alpha (D). Filled red areas represent isotype-PE control and blue lines represent IL-28Ralpha-PE.

Mentions: IFN-lambda1, IFN-lambda2 and IFN-lambda3 act by binding to the IFN-lambdaR. We examined the expression of the IFN-lambdaR-specific IL-28Ralpha chain on pDC (Fig. 5A), resting CD4+ cells (Fig. 5B) and on CD4+ cells that had been activated for 24 h with anti-CD3 (Fig. 5C) or cultured for 24 h in the presence of IFN-alpha (Fig. 5D). We found that neither resting nor activated CD4+ T-cells expressed any detectable levels of IL-28Ralpha whereas low levels could be detected on pDC.


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

Nordström I, Eriksson K - PLoS ONE (2012)

CD4+ T-cells do not express IL-28Ralpha.Resting or activated cord blood mononuclear cells were analyzed for IL-28Ralpha expression using FACS. IL-28Ralpha expression (histograms) on pDC (A) or CD4+ T-cells obtained directly upon isolation (B) or after 24 h incubation with anti-CD3 (C) or recombinant human IFN-alpha (D). Filled red areas represent isotype-PE control and blue lines represent IL-28Ralpha-PE.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0038683-g005: CD4+ T-cells do not express IL-28Ralpha.Resting or activated cord blood mononuclear cells were analyzed for IL-28Ralpha expression using FACS. IL-28Ralpha expression (histograms) on pDC (A) or CD4+ T-cells obtained directly upon isolation (B) or after 24 h incubation with anti-CD3 (C) or recombinant human IFN-alpha (D). Filled red areas represent isotype-PE control and blue lines represent IL-28Ralpha-PE.
Mentions: IFN-lambda1, IFN-lambda2 and IFN-lambda3 act by binding to the IFN-lambdaR. We examined the expression of the IFN-lambdaR-specific IL-28Ralpha chain on pDC (Fig. 5A), resting CD4+ cells (Fig. 5B) and on CD4+ cells that had been activated for 24 h with anti-CD3 (Fig. 5C) or cultured for 24 h in the presence of IFN-alpha (Fig. 5D). We found that neither resting nor activated CD4+ T-cells expressed any detectable levels of IL-28Ralpha whereas low levels could be detected on pDC.

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