Plasmacytoid dendritic cells and the control of herpesvirus infections

Abstract

Type-I interferons (IFN-I) are cytokines essential for vertebrate antiviral defense, including against herpesviruses. IFN-I have potent direct antiviral activities and also mediate a multiplicity of immunoregulatory functions, which can either promote or dampen antiviral adaptive immune responses. Plasmacytoid dendritic cells (pDCs) are the professional producers of IFN-I in response to many viruses, including all of the herpesviruses tested. There is strong evidence that pDCs could play a major role in the initial orchestration of both innate and adaptive antiviral immune responses. Depending on their activation pattern, pDC responses may be either protective or detrimental to the host. Here, we summarize and discuss current knowledge regarding pDC implication in the physiopathology of mouse and human herpesvirus infections, and we discuss how pDC functions could be manipulated in immunotherapeutic settings to promote health over disease.

Keywords: herpesvirus type 1; herpesvirus type 2; human cytomegalovirus; immunotherapy; mouse cytomegalovirus; plasmacytoid dendritic cell; type-I interferon.

Figure 1.

Cytokine and chemokine mRNA expression by pDCs and cDCs isolated from MCMV-infected animals at 36 hours post-challenge. pDCs (red circles), CD8α cDCs (blue diamonds) and CD11b cDCs (green triangles) were purified from C57BL/6 mice injected with vehicle (open symbols) or infected with MCMV for 36 h (closed symbols). Pangenomic microarray experiments were performed with the total mRNA isolated from these cell populations [43]. The expression of mRNA (Y-axis, in arbitrary units in log10 scale) encoding various innate cytokines and chemokines (X-axis) in the three DC subsets studied is represented. Genes were classified in 5 groups accordingly to their pattern of expression across the 6 types of biological samples examined, using the GeneCluster software. Group 1 corresponds to the IFN-I genes which are undetectable or expressed only at very low level under steady state conditions, but which are induced to extremely high levels specifically in pDCs after infection. Group 2 corresponds to genes that are induced in all DC subsets but to a higher level in pDCs. Group 3 correspond to genes that are strongly induced to a comparable extent in all three DC subsets. Group 4 corresponds to genes induced to higher levels in cDCs as compared to pDCs. Group 5 corresponds to genes induced to higher levels specifically in CD8α cDCs.

Scheme 1.

Modulation of innate and adaptive immune responses by herpesvirus-activated pDCs. pDCs are able to sense infection with herpesviruses through TLR9 and/or TLR7. The triggering of these receptors in specialized endosomes, where they are preassembled with the MyD88 adapter molecule and the IRF7 transcription factor in multimolecular complexes, leads to the phosphorylation of IRF7 and its translocation to the nucleus where it associates with other partners to constitute a transcription initiation complex (TIC) able to induce the expression of IFN-I and other target genes. Largely due to their production of innate cytokines or chemokines, pDCs can exert a variety of stimulatory or inhibitory functions on other innate or adaptive immune cell types. The global effect of pDC responses on the overall immune response and on the promotion of health versus disease depends on the combination and levels of the cytokines that they produce as discussed in Scheme 2.

Scheme 2.

Impact of the fine tuning of pDC activation on the promotion of health versus disease. During herpesvirus infections, disease can result either from immune failure to control viral replication early or from the development of immunopathology. Weak pDC activation could contribute to disease in the former case, and excessive pDC activation in the latter case. Immunopathology can cause immune-mediated damage to vital organs and/or compromise the ability of adaptive immunity to control viral replication later. Thus, a significant but controlled pDC activation is required to promote health over disease, by allowing early control of viral replication while not causing significant immunopathology. Therapeutic protocols aimed at boosting or dampening pDC responses could thus help to reach this balance and to fight disease under defined clinical conditions, as discussed in the body of this review.