Atherosclerosis represents a chronic inflammatory condition in arterial walls, where local immune cells significantly contribute to disease progression. This study employed various in situ immunological techniques to investigate the specific roles of aortic dendritic cell (DC) subsets in atherosclerotic animal models, distinguishing between normal and diseased immune contexts. Our findings revealed that aortic DCs, particularly the cDC1 subset, played a critical role in facilitating CD8+ T cell activation through antigen presentation. Additionally, atherosclerosis-induced increases in GM-CSF levels enhanced CCR7 expression on aortic monocyte-derived DCs, promoting their recruitment and IL-12 production for Th1 differentiation. Notably, immunizing pre-atherosclerotic mice with DC-presented antigens or transferring aortic DCs from atherosclerotic mice resulted in accelerated disease onset. This research elucidates the adaptive immune functions of aortic DCs, offering insights into the cellular mechanisms driving aortic inflammation and potential therapeutic targets for atherosclerosis management.
© 2024 The Author(s).

The COVID-19 pandemic reminded us of the urgent need for new antivirals to control emerging infectious diseases and potential future pandemics. Immunotherapy has revolutionized oncology and could complement the use of antivirals, but its application to infectious diseases remains largely unexplored. Nucleoside analogs are a class of agents widely used as antiviral and anti-neoplastic drugs. Their antiviral activity is generally based on interference with viral nucleic acid replication or transcription. Based on our previous work and computer modeling, we hypothesize that antiviral adenosine analogs, like remdesivir, have previously unrecognized immunomodulatory properties which contribute to their therapeutic activity. In the case of remdesivir, we here show that these properties are due to its metabolite, GS-441524, acting as an Adenosine A2A Receptor antagonist. Our findings support a new rationale for the design of next-generation antiviral agents with dual - immunomodulatory and intrinsic - antiviral properties. These compounds could represent game-changing therapies to control emerging viral diseases and future pandemics.
© 2024. The Author(s).

Phosphatase and tensin homolog (PTEN) is vital for B cell development, acting as a key negative regulator in the PI3K signaling pathway. We used CD23-cre to generate PTEN-conditional knockout mice (CD23-cKO) to examine the impact of PTEN mutation on peripheral B cells. Unlike mb1-cre-mediated PTEN deletion in early B cells, CD23-cKO mutants exhibited systemic inflammation with increased IL-6 production in mature B cells upon CpG stimulation. Inflammatory B cells in CD23-cKO mice showed elevated phosphatidylinositol 3-phosphate [PI(3)P] levels and increased TLR9 endosomal localization. Pharmacological inhibition of PI(3)P synthesis markedly reduced TLR9-mediated IL-6. Single-cell RNA-sequencing (RNA-seq) revealed altered endocytosis, BANK1, and NF-κB1 expression in PTEN-deficient B cells. Ectopic B cell receptor (BCR) expression on non-inflammatory mb1-cKO B cells restored BANK1 and NF-κB1 expression, enhancing TLR9-mediated IL-6 production. Our study highlights PTEN as a crucial inflammatory checkpoint, regulating TLR9/IL-6 axis by fine-tuning PI(3)P homeostasis. Additionally, BCR downregulation prevents the differentiation of inflammatory B cells in PTEN deficiency.
© 2024 The Author(s).

FLT3-L-dependent classical dendritic cells (cDCs) recruit anti-tumor and tumor-protecting lymphocytes. We evaluate cancer growth in mice with low, normal, or high levels of cDCs. Paradoxically, both low or high numbers of cDCs improve survival in mice with melanoma. In low cDC context, tumors are restrained by the adaptive immune system through influx of effector T cells and depletion of Tregs and NK cells. High cDC numbers favor the innate anti-tumor response, with massive recruitment of activated NK cells, despite high Treg infiltration. Anti CTLA-4 but not anti PD-1 therapy synergizes with FLT3-L therapy in the cDCHi but not in the cDCLo context. A combination of cDC boost and Treg depletion dramatically improves survival of tumor-bearing mice. Transcriptomic data confirm the paradoxical effect of cDC levels on survival in several human tumor types. cDCHi-TregLo state in such patients predicts best survival. Modulating cDC numbers via FLT3 signaling may have therapeutic potential in human cancer.
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Visceral leishmaniasis (VL) in the Americas is a chronic systemic disease caused by infection with Leishmania infantum parasites. The toxicity of antileishmanial drugs, long treatment course and limited efficacy are significant concerns that hamper adequate treatment against the disease. Studies have shown the promise of an immunotherapeutics approach, combining antileishmanial drugs to reduce the parasitism and vaccine immunogens to activate the host immune system. In the current study, we developed an immunotherapy using a recombinant T cell epitope-based chimeric protein, ChimT, previously shown to be protective against Leishmania infantum, with the adjuvant monophosphoryl lipid A (MPLA) and amphotericin B (AmpB) as the antileishmanial drug. BALB/c mice were infected with L. infantum stationary promastigotes and later they received saline or were treated with AmpB, MPLA, ChimT/Amp, ChimT/MPLA or ChimT/MPLA/AmpB. The combination of ChimT/MPLA/AmpB significantly reduced the parasite load in mouse organs (p < 0.05) and induced a Th1-type immune response, which was characterized by higher ratios of anti-ChimT and anti-parasite IgG2a:IgG1 antibodies, increased IFN-γ mRNA and IFN-γ and IL-12 cytokines and accompanied by lower levels of IL-4 and IL-10 cytokines, when compared to other treatments and controls (all p < 0.05). Organ toxicity was also lower with the ChimT/MPLA/AmpB immunotherapy, suggesting that the inclusion of the vaccine and adjuvant ameliorated the toxicity of AmpB to some degree. In addition, the ChimT vaccine alone stimulated in vitro murine macrophages to significantly kill three different internalized species of Leishmania parasites and to produce Th1-type cytokines into the culture supernatants. To conclude, our data suggest that the combination of ChimT/MPLA/AmpB could be considered for further studies as an immunotherapy for L. infantum infection.