Preprint Club
A cross-institutional Journal Club Initiative

Keywords

●  Plasmacytoid Dendritic Cells

●  Interferon

●  Viral infections

Main Findings

Interferons (IFNs) play a central role in immunity. They trigger intrinsic immune responses against infections by activating protective transcriptional programs and prompting innate and adaptive immune responses. IFN production is tightly regulated, as disruption of this delicate balance can lead to pathological and deleterious effects. An excess of IFN can cause overactivation of the immune system and a cascade of amplifying events such as the cytokine storm. In this preprint, Ngo and colleagues answer on the instrumental role of the major producers of type I IFN (IFN-I). In a true tour de force for immunology, the authors evaluate the role of plasmacytoid dendritic cells (pDCs) and the contribution of their IFN-I production to pathology in different viral infections.

pDCs are the main source of IFN-Is and their role in infection has long been thought to be protective. pDCs sense viral RNA and DNA through TLR7 and TLR9 respectively leading to IFN-I production, triggering antiviral immunity. Previous mouse models have been unsuitable for properly addressing the role of pDCs, resulting in conflicting findings. To date, the most precise model for depleting pDCs (based on BDCA2) released high levels of IFN-I after depletion, confounding the results on IFN-I production. Here, Ngo et al. develop a model to deplete pDCs based on double marker (SIGLECH and PACSIN1) expression that effectively ablates pDCs without major effects on other myeloid and lymphoid lineages.

Using this model, the authors evaluate the role of pDCs and their role as sources for IFN-I in systemic and respiratory infections.

In systemic mouse cytomegalovirus infection (mCMV), pDCs ablation led to a drastic reduction of IFN-Is. IFN-alpha production was most affected as IRF7 is constitutively expressed in pDCs for a rapid IFN-I induction. Ablating the major source of IFN-I led to a reduction in IFN-stimulated genes (ISGs) expression but the production of other pro-inflammatory cytokines was unaffected. Despite its role in antiviral immunity, pDCs didn’t seem to play a role in viral clearance nor affected NK and cDCs activation.

Using an influenza A viral (IAV) strain responsible for severe pneumonia, the authors show the key role of pDCs in promoting life-threatening conditions through pDC-produced IFN by TLR7-dependent mechanisms. Interestingly, selective inactivation of the TLR7/Myd88/IRF7 signalling in pDCs restored resistance to infection and the detrimental contribution of IFNs; offering a potential target for pathologies with overactivation. However, IFN-I induction via TLR7 appeared protective in SARS-COV-2 infection despite confirming a detrimental role for pDCs in survival that was worse for males.

Of relevance, cytokines known to promote acute respiratory distress syndrome (ARDS) were reduced in pDC-less mice in late stages of influenza infection. Intrinsic immunity was unaffected in pDC-less mice, providing evidence that IFN-I produced by other cell types is sufficient to activate antiviral immunity.

The authors also highlight the contribution of pDCs to pathology and tissue damage. pDCs were found to localise in highly infected and inflamed areas in the lung, correlating with disrupted lung integrity and increased permeability.

These results show that not only are pDCs dispensable for antiviral immunity but the IFN-I they produce is responsible for tissue damage and reduced survival in viral infections. This certainly raises many questions about the role of pDCs in immunity and why they have been conserved through evolution. In future studies, it will be key to understand whether their functions are more important in the setting of low-dose inoculums or homeostatic conditions. In addition, future research should revisit the contribution of pDCs to immune memory, cancer and autoimmune diseases.

Limitations

Although the study is very complete, and while the authors describe NK and cDC activation in mCMV infection, it would be nice to understand cell activation and recruitment in the lung for respiratory infections when doing histological studies. It would also have been interesting to have a re-challenge experiment to evaluate the potency of the memory response in pDC-less mice.

Since pDCs constitutively express IRF7, it would also be informative to get into more detail on the differences between INF-alpha and IFN-beta in the pathological effects. Moreover, IFN-III is not further evaluated through the paper, despite pDCs being producers of IFN-III.

The pDC-less model has increased cDC1 but there is no characterisation on whether this model has reduced precursors (IPCs) and therefore on how long this ablation lasts, and what could be the long-term consequences.

Significance/Novelty

This study provides new and clear insights into the role of pDCs in viral infection. The authors have developed a reliable model that effectively ablates pDCs without significantly affecting other cell lineages. 

The results offer groundbreaking knowledge to the field of immunology and may prompt a reevaluation of many established concepts regarding pDCs. Additionally, this study raises numerous new questions about the role of pDCs, leaving us with the mystery of the actual function of these cells, which, according to this study, appear to be more detrimental than beneficial.

Credit

Reviewed by Ester Gea-Mallorquí as part of a cross-institutional journal club between the Icahn School of Medicine at Mount Sinai, the University of Oxford, the Karolinska Institute and the University of Toronto.

The author declares no conflict of interests in relation to their involvement in the review.