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.
Highlights
The recently discovered type III IFNs share many of the antiviral properties of type I IFNs
The Human herpesvirus type 6B (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)
In this study we show that inactivated HHV-6B is a potent inducer of IFN-lambda1 but not IFN-lambda2 in plasmacytoid dendritic cells (pDC) through a TLR9-dependent signaling pathway
Summary
The recently discovered type III IFNs share many of the antiviral properties of type I IFNs. All three IFN-lambdas utilize a common distinct receptor, the IFN-lambdaR, which is composed of the IL10R2 chain and the unique IL-28Ralpha chain [2,3]. The IFNlambdaR is expressed at high densities on epithelial cells [3] but IL-28Ralpha transcripts might be found in other cells including blood lymphocytes [2]. Binding of IFN-lambda to its receptor induces a signaling response similar to that obtained by type I IFNs [1], even though the intensity of the IFN-lambda response is generally weaker [1,4]. The anti-viral effects obtained by IFN-lambda protects against some but not all viral infections, and preferentially those that occur at mucosal surfaces [5,6]
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