HHV-6B induces IFN-lambda1 responses in cord plasmacytoid dendritic cells through TLR9.
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.
Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Inger
I
Nordström
Kristina
K
Eriksson
D000704:Analysis of Variance; D016764:Cell Polarity / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology; D005434:Flow Cytometry; D015654:Herpesvirus 6, Human / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000276:immunology*; D000095022:Interferon Lambda
D007372:Interferons; D007378:Interleukins; D051217:Toll-Like Receptor 9; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C495371:TLR9 protein, human