Human plasmacytoid dendritic cells regulate immune responses to Epstein-Barr virus (EBV) infection and delay EBV-related mortality in humanized NOD-SCID mice

Abstract

Epstein-Barr virus (EBV) is associated with post-transplant lymphoproliferative disease (PTLD),which is a leading cause of cancer death in transplant recipients. We investigated the role of plasmacytoid dendritic cells (PDC) in the development of EBV infection and the onset of lymphoproliferative disease (LPD) in humanized NOD-SCID mice, and studied the effect of EBV on PDC function. NOD-SCID mice reconstituted with PDC-depleted peripheral blood mononuclear cells (PBMC) from EBV IgG+ve human donors had significantly enhanced mortality from disseminated EBV infection (median survival 43 days) compared to PBMC-only mice (median survival 72 days, log rank p-value<0.05). Mice reconstituted with PDC-enriched PBMC challenged with EBV exhibited delayed mortality from EBV-LPD (median survival 80 days) compared to PBMC-only mice challenged with EBV (median survival 50 days, log rank p-value<0.05). EBV-stimulated PDC produced interferon (IFN)- and promoted the activation of NK cells and IFN--producing CD3+ T cells. PDC activation of CD3+ T cells in response to EBV stimulation was cell-cell contact dependent, in part mediated by toll-like receptor (TLR)-9 signalling that was inhibited by chloroquine and TLR-9 inhibitory CpG. Thus PDC play an important role in anti-EBV cellular immune responses that may be targets for manipulation in novel strategies for the treatment of PTLD.