Plasmacytoid dendritic cells (pDCs) are a rare but specialized immune cell subset that represents an important link between innate and adaptive immunity. The most known function of pDCs is their capability to respond with high amounts of type I interferons (IFNs) to viral stimuli. Despite their immunogenic functions, especially in anti-viral immunity, pDCs are also known to exert tolerogenic functions. PDCs were found to express the serine protease granzyme B (GrB). PDC-derived GrB was shown to suppress T cell proliferation indicating that a regulatory mechanism is mediated by this molecule. In this study we evaluated the effects of diverse viral stimuli (vaccine-derived live attenuated varicella-zoster virus (VZV), ultraviolet light (UV)-inactivated cytomegalovirus (CMV), replicable Epstein-Barr virus (EBV) and human immunodeficiency virus 1 (HIV-1) on human pDC-derived GrB, the phenotype and function of human pDCs.
GrB production and secretion were differentially regulated by the viral stimuli. VZV and CMV diminished GrB production in pDCs whereas EBV and HIV-1 increased GrB secretion indicating that GrB expression by pDCs is virus-specifically regulated. Robust IFN-α secretion was only observed for VZV and CMV. In contrast, EBV and HIV-1 induced only very low levels of IFN-α. On the contrary, HIV-1-infected T cells led to relevant IFN-α secretion by pDCs in pDC-CD4+ T cell co-cultures. The herpesviruses VZV and CMV, but not EBV and HIV-1 induced a rather immunogenic phenotype in pDCs. CMV and VZV upregulated human leukocyte antigen (HLA)-ABC, VZV additionally Cluster of differentiation (CD)54 on the cell surface of pDCs. CMV- and VZV-pre-stimulated pDCs were able to enhance T cell proliferation in MLRs with CD4+ T cells whereas EBV and particularly HIV-1 failed to provoke significant T cell proliferation. Overall our MLR results inversely correlated with the regulation of GrB in pDCs and support the finding that pDC-derived GrB inhibits T cell proliferation.
Our findings contribute to further understand the interaction of viruses with pDCs. PDCs might orchestrate immune responses, especially specific T cell responses, in the course of viral infections via GrB production. Virus-specific lower pDC-GrB levels might rather facilitate, high levels might limit T cell responses. PDC-derived GrB might hence represent a regulatory effector molecule in anti-viral immunity
