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Plasmacytoid Dendritic cells (pDCs) are the most potent producers of interferons, which are critical antiviral cytokines. pDC development is, however, compromised following a viral infection, and this phenomenon, as well as its relationship to conventional (c)DC development is still incompletely understood. By using lymphocytic choriomeningitis virus (LCMV) infection in mice as a model system, we observed that DC progenitors skewed away from pDC and towards cDC development during in vivo viral infection. Subsequent characterization of the transcriptional and epigenetic landscape of fms-like tyrosine kinase 3 + (Flt3 + ) DC progenitors and follow-up studies revealed increased apoptosis and reduced proliferation in different individual DC-progenitors as well as a profound IFN-I-dependent ablation of pre-pDCs, but not pre-DC precursor, after both acute and chronic LCMV infections. In addition, integrated genomic analysis identified altered activity of 34 transcription factors in Flt3 + DC progenitors from infected mice, including two regulators of Glucocorticoid (GC) responses. Subsequent studies demonstrated that addition of GCs to DC progenitors led to downregulated pDC-primed-genes while upregulating cDC-primed-genes, and that endogenous GCs selectively decreased pDC, but not cDC, numbers upon in-vivo LCMV infection. These findings demonstrate a significant ablation of pre-pDCs in infected mice and identify GCs as suppressors of pDC generation from early progenitors. This provides an explanation for the impaired pDC development following viral infection and links pDC generation to the hypothalamic-pituitary-adrenal axis., Significance Statement: Plasmacytoid dendritic cells (pDCs) play critical roles in antiviral responses. However, adaptations of DC progenitors lead to compromised pDC generation after viral infection. Here, we characterized the transcriptional and epigenetic landscapes of DC progenitors after infection. We observed widespread changes in gene expression and chromatin accessibility, reflecting shifts in proliferation, apoptosis, and differentiation potential into various DC subsets. Notably, we identified alterations in the predicted activity of 34 transcription factors, including two regulators of glucocorticoid responses. Our data demonstrate that glucocorticoids inhibit pDC generation by reprogramming DC progenitors. These findings establish a molecular framework for understanding how DC progenitors adapt to infection and highlight the role of glucocorticoid signaling in this process.

Type I Interferons (IFN-I) are central to host protection against viral infections 1 . While any cell can produce IFN-I, Plasmacytoid Dendritic Cells (pDCs) make greater quantities and more varieties of these cytokines than any other cell type 2 . However, following an initial burst of IFN- I, pDCs lose their exceptional IFN-I production capacity and become "exhausted", a phenotype that associates with enhanced susceptibility to secondary infections 3-5 . Despite this apparent cost for the host, pDC exhaustion is conserved across multiple species and viral infections, but the underlying mechanisms and the potential evolutionary advantages are not well understood. Here we characterize pDC exhaustion and demonstrate that it is associated with a reduced capacity of pDCs to engage both oxidative and glycolytic metabolism. Mechanistically, we identify lactate dehydrogenase B (LDHB) as a novel positive regulator of pDC IFN-I production in mice and humans, show that LDHB deficiency is associated with suppressed IFN-I production, pDC metabolic capacity, and viral control following a viral infection, and demonstrate that preservation of LDHB expression is sufficient to partially restore exhausted pDC function in vitro and in vivo . Furthermore, restoring LDHB in vivo in exhausted pDCs increased IFNAR dependent infection- associated pathology. Therefore, our work identifies a novel and conserved mechanism for balancing immunity and pathology during viral infections, while also providing insight into the highly preserved but previously unexplained phenomenon of pDC exhaustion.

The IL-6 cytokine family signals through the common signal transduction molecule gp130 combined with a cytokine-specific receptor. Gp130 signaling on CD4 T cells is vital in controlling chronic infection of mice with lymphocytic choriomeningitis virus clone 13 (LCMV Cl13), but the precise role of individual members of the IL-6 cytokine family is not fully understood. Transcriptional analysis highlighted the importance of gp130 signaling in promoting key processes in CD4 T cells after LCMV Cl13 infection, particularly genes associated with T follicular helper (Tfh) cell differentiation and IL-21 production. Further, Il27r -/- Il6ra -/- mice failed to generate antibody or CD8 T-cell immunity and to control LCMV Cl13. Transcriptomics and phenotypic analyses of Il27r -/- Il6ra -/- Tfh cells revealed that IL-6R and IL-27R signaling was required to activate key pathways within CD4 T cells. IL-6 and IL-27 signaling has distinct and overlapping roles, with IL-6 regulating Tfh differentiation, IL-27 regulating CD4 T cell survival, and both redundantly promoting IL-21., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Harker, Greene, Barnett, Bao, Dolgoter and Zuniga.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has caused millions of deaths in the past two years. Although initially little was understood about this virus, recent research has significantly advanced and landed interferons (IFNs) in the spotlight. While Type I and III IFN have long been known as central to antiviral immunity, in the case of COVID-19 their role was initially controversial. However, the protective function of IFN is now well supported by the identification of human deficiencies in IFN responses as a predictor of disease severity. Here, we will review the cell types and pathways that lead to IFN production as well as the importance of IFN timing and location for disease outcome. We will further discuss the mechanisms that SARS-CoV-2 uses to evade IFN responses, and the current efforts to implement IFNs as therapeutics in the treatment of COVID-19. It is essential to understand the relationships between SARS-CoV-2 and IFN to better inform treatments that exploit IFN functions to alleviate COVID-19., (© 2022 The Authors. Immunological Reviews published by John Wiley & Sons Ltd.)

Emerging immunotherapies offer a new hope for cancer patients but are not always effective even when a tumor is recognized by the immune system. Baldominos and colleagues address this challenge by characterizing a resilient niche of metabolically unique quiescent cancer cells (QCCs) that resist T cell-mediated control., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Type I Interferons (IFN-I) are a family of potent antiviral cytokines that act through the direct restriction of viral replication and by enhancing antiviral immunity. However, these powerful cytokines are a caged lion, as excessive and sustained IFN-I production can drive immunopathology during infection, and aberrant IFN-I production is a feature of several types of autoimmunity. As specialized producers of IFN-I plasmacytoid (p), dendritic cells (DCs) can secrete superb quantities and a wide breadth of IFN-I isoforms immediately after infection or stimulation, and are the focus of this review. Notably, a few days after viral infection pDCs tune down their capacity for IFN-I production, producing less cytokines in response to both the ongoing infection and unrelated secondary stimulations. This process, hereby referred to as "pDC exhaustion", favors viral persistence and associates with reduced innate responses and increased susceptibility to secondary opportunistic infections. On the other hand, pDC exhaustion may be a compromise to avoid IFN-I driven immunopathology. In this review we reflect on the mechanisms that initially induce IFN-I and subsequently silence their production by pDCs during a viral infection. While these processes have been long studied across numerous viral infection models, the 2019 coronavirus disease (COVID-19) pandemic has brought their discussion back to the fore, and so we also discuss emerging results related to pDC-IFN-I production in the context of COVID-19.

Plasmacytoid dendritic cells (pDCs) are specialized producers of Type I interferon (IFN-I) that promote anti-viral and anti-tumor immunity. However, chronic infections and cancer inhibit pDC-derived IFN-I. While the mechanisms of this inhibition are multifarious they can be classified broadly into two categories: i) reduction or ablation of pDC IFN-I-production capacity (functional exhaustion) and/or ii) decrease in pDC numbers (altered population dynamics). Recent work has identified many processes that contribute to suppression of pDC-derived IFN-I during chronic infections and cancer, including sustained stimulation through Toll Like Receptors (TLRs), inhibitory microenvironments, inhibitory receptor ligation, and reduced development from bone marrow progenitors and apoptosis. Emerging success leveraging pDCs in treatment of disease through TLR activation illustrates the therapeutic potential of targeting pDCs. Deeper understanding of the systems that limit pDC-derived IFN-I has the potential to improve these emerging therapies as well as help devising new approaches that harness the outstanding IFN-I-production capacity of pDCs., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

In a recent issue of Nature, Borges da Silva et al. (2018) reveal that P2RX7, a receptor for extracellular ATP, promotes CD8 T cell memory by enhancing metabolic fitness. This work links an ancient "danger" signal with long-term immunity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Natural Killer (NK) cells are essential for control of viral infection and cancer. NK cells express NKG2D, an activating receptor that directly recognizes NKG2D ligands. These are expressed at low level on healthy cells, but are induced by stresses like infection and transformation. The physiological events that drive NKG2D ligand expression during infection are still poorly understood. We observed that the mouse cytomegalovirus encoded protein m18 is necessary and sufficient to drive expression of the RAE-1 family of NKG2D ligands. We demonstrate that RAE-1 is transcriptionally repressed by histone deacetylase inhibitor 3 (HDAC3) in healthy cells, and m18 relieves this repression by directly interacting with Casein Kinase II and preventing it from activating HDAC3. Accordingly, we found that HDAC inhibiting proteins from human herpesviruses induce human NKG2D ligand ULBP-1. Thus our findings indicate that virally mediated HDAC inhibition can act as a signal for the host to activate NK-cell recognition., Competing Interests: The authors declare that no competing interests exist.

Recognition and elimination of tumor cells by the immune system is crucial for limiting tumor growth. Natural killer (NK) cells become activated when the receptor NKG2D is engaged by ligands that are frequently upregulated in primary tumors and on cancer cell lines. However, the molecular mechanisms driving NKG2D ligand expression on tumor cells are not well defined. Using a forward genetic screen in a tumor-derived human cell line, we identified several novel factors supporting expression of the NKG2D ligand ULBP1. Our results show stepwise contributions of independent pathways working at multiple stages of ULBP1 biogenesis. Deeper investigation of selected hits from the screen showed that the transcription factor ATF4 drives ULBP1 gene expression in cancer cell lines, while the RNA-binding protein RBM4 supports ULBP1 expression by suppressing a novel alternatively spliced isoform of ULBP1 mRNA. These findings offer insight into the stress pathways that alert the immune system to danger.