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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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HHV-6B induces the production of IFN-alpha, IFN-lambda1 but not IFN-lambda2 in pDC in a TLR9-dependent fashion.Purified cord pDC were exposed to inactivated HHV-6B in the presence or absence of G-ODN, a TLR9-specific inhibitor. The levels of IFN-alpha (A; n = 20), IFN-lambda1 (B; n = 15) and IFN-lambda2 (C; n = 5) were analyzed in 24h culture supernatants. Data are expressed as mean + SEM. **  =  p<0.01, ***  =  p<0.001 using ANOVA with Bonferroni's multiple comparison test. The levels of IFN-lambda1 and IFN-lambda2 were also assessed over a 72 h time-period (D; n = 3).
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pone-0038683-g001: HHV-6B induces the production of IFN-alpha, IFN-lambda1 but not IFN-lambda2 in pDC in a TLR9-dependent fashion.Purified cord pDC were exposed to inactivated HHV-6B in the presence or absence of G-ODN, a TLR9-specific inhibitor. The levels of IFN-alpha (A; n = 20), IFN-lambda1 (B; n = 15) and IFN-lambda2 (C; n = 5) were analyzed in 24h culture supernatants. Data are expressed as mean + SEM. **  =  p<0.01, ***  =  p<0.001 using ANOVA with Bonferroni's multiple comparison test. The levels of IFN-lambda1 and IFN-lambda2 were also assessed over a 72 h time-period (D; n = 3).

Mentions: We have previously shown that inactivated HHV-6B induces a strong IFN-alpha response in cord pDC, which we confirm in Fig. 1A. In addition, we show that inactivated HHV-6B also induces high levels of IFN-lambda1 from pDC (Fig. 1B), but no or little IFN-lambda2 (Fig. 1C). The lack of induction of IFN-lambda2 was not dependent on the kinetics, at these low levels remained constant over 72 h (Fig. 1D). It should be noted that the sensitivity of the ELISAs varied from 10 pg/ml for IFN-alpha, 60 pg/ml for IFN-lambda1 and 100 pg/ml for IFN-lambda2. This means that we have not been able to detect potential low IFN-lambda2 responses. The HHV-6B-induced production of both IFN-alpha and IFN-lambda1 was dependent on TLR9 as it was completely abolished in the presence of a TLR9-specific inhibitor, G-ODN (Fig. 1A–B).


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

Nordström I, Eriksson K - PLoS ONE (2012)

HHV-6B induces the production of IFN-alpha, IFN-lambda1 but not IFN-lambda2 in pDC in a TLR9-dependent fashion.Purified cord pDC were exposed to inactivated HHV-6B in the presence or absence of G-ODN, a TLR9-specific inhibitor. The levels of IFN-alpha (A; n = 20), IFN-lambda1 (B; n = 15) and IFN-lambda2 (C; n = 5) were analyzed in 24h culture supernatants. Data are expressed as mean + SEM. **  =  p<0.01, ***  =  p<0.001 using ANOVA with Bonferroni's multiple comparison test. The levels of IFN-lambda1 and IFN-lambda2 were also assessed over a 72 h time-period (D; n = 3).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3368904&req=5

pone-0038683-g001: HHV-6B induces the production of IFN-alpha, IFN-lambda1 but not IFN-lambda2 in pDC in a TLR9-dependent fashion.Purified cord pDC were exposed to inactivated HHV-6B in the presence or absence of G-ODN, a TLR9-specific inhibitor. The levels of IFN-alpha (A; n = 20), IFN-lambda1 (B; n = 15) and IFN-lambda2 (C; n = 5) were analyzed in 24h culture supernatants. Data are expressed as mean + SEM. **  =  p<0.01, ***  =  p<0.001 using ANOVA with Bonferroni's multiple comparison test. The levels of IFN-lambda1 and IFN-lambda2 were also assessed over a 72 h time-period (D; n = 3).
Mentions: We have previously shown that inactivated HHV-6B induces a strong IFN-alpha response in cord pDC, which we confirm in Fig. 1A. In addition, we show that inactivated HHV-6B also induces high levels of IFN-lambda1 from pDC (Fig. 1B), but no or little IFN-lambda2 (Fig. 1C). The lack of induction of IFN-lambda2 was not dependent on the kinetics, at these low levels remained constant over 72 h (Fig. 1D). It should be noted that the sensitivity of the ELISAs varied from 10 pg/ml for IFN-alpha, 60 pg/ml for IFN-lambda1 and 100 pg/ml for IFN-lambda2. This means that we have not been able to detect potential low IFN-lambda2 responses. The HHV-6B-induced production of both IFN-alpha and IFN-lambda1 was dependent on TLR9 as it was completely abolished in the presence of a TLR9-specific inhibitor, G-ODN (Fig. 1A–B).

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