Biology subjects

Blanchet, F. P.

Publications and source records attributed to Blanchet, F. P..

4 recordsLinked to original sources

bioRxiv2025

Adenovirus-based vaccines transduce and activate human Langerhans cells

Langerhans cells (LCs) are specialized antigen-presenting cells (APCs) located in the epidermis and mucosal tissues and play a critical role in host immune surveillance. The role of LCs in antiviral responses is well established, but their involvement in vaccine-induced immunity, particularly with human adenovirus (HAdV) vectors, remains poorly understood. Here, we investigated how human LCs respond to HAdV vectors commonly used in vaccine development. We used CD34+ hematopoietic stem cells differentiated into LCs (CD34-LCs) to evaluate their ability to internalize replication-defective HAdV types C5, D26, and B35 vectors. CD34-LCs took up all three vectors, which induced an antiviral and pro-inflammatory cytokine response and morphological changes indicative of activation. To address the role of LCs in a more physiologically relevant setting, we injected human skin explants with the HAdV vectors. Epidermal LCs were recruited to the injection site and took up the vectors. Moreover, we show that the presence of lactoferrin (Lf), an antimicrobial protein, enhances HAdV uptake. Overall, our findings highlight a key role for LCs in the initiation of immune responses to HAdV-based vaccines. This work lays a foundation for strategies aiming to enhance vaccine efficacy by modulating LC activation and targeting. IMPORTANCEHAdV vectors are widely used in vaccine development, but the role of LCs, the epidermal immune sentinels, remains poorly defined. Here, we show using in vitro and ex vivo human systems that LCs efficiently detect, internalize and express transgenes delivered by three HAdV species. Because LCs link innate and adaptive immunity, the direct and indirect uptake of HAdVs may contribute to vaccine efficacy.

immunology↗

bioRxiv2024

Human plasma metabolic environment favours HIV replication in primary CD4 T lymphocytes

Cellular metabolism supports all viral replication steps and the metabolic state of infected cells is therefore a key factor influencing viral infections. Human Immunodeficiency virus (HIV) remains latent in resting CD4 T lymphocytes but actively replicates in activated CD4 T cells due to enhanced energy metabolism. Here, using the recently developed Human Plasma-Like Medium (HPLM) that mimics physiological plasma concentration of metabolites, we investigated how this near-physiologic environment modulates HIV-1 infection in primary CD4 T cells. Compared to the conventional culture medium (RPMI), HPLM enhanced HIV-1 infection in CD4 T cells despite similar levels of cell activation, proliferation and expression of viral receptor. In contrast with previous studies in RPMI, HPLM increased infection while decreasing energy metabolism and affecting other non-energetic metabolic pathways. Adjusting levels of several metabolites in RPMI and HPLM, we uncovered that the amino acids balance rather than the energy metabolism favoured HIV-1 replication in this system. Overall, our study used near-physiological conditions to better define metabolic dependencies of viral infections and highlights previously overlooked non-energetic metabolism pathways important for HIV-1 infection.

microbiology↗

bioRxiv2022

The crosstalk between DNA-PK and cGAS drives tumor immunogenicity

Cytosolic DNAs promote inflammatory responses upon detection by the cyclic GMP-AMP (cGAMP) synthase (cGAS). It has been thus suggested that cGAS downregulation is an immune escape strategy harnessed by tumor cells. Here, we used glioblastoma cells that lack cGAS to question whether alternative DNA detection pathways can promote pro-inflammatory signaling. We show that the DNA-PK DNA repair complex drives cGAS independent inflammatory responses but that its catalytic activity is required for cGAS-dependent cGAMP production and optimal downstream signaling. We further show that the cooperation between DNA-PK and cGAS favors the expression of chemokines that promote macrophage recruitment in the tumor microenvironment, a process that impaired early tumorigenesis but correlated with poor outcome. Thus, our study supports that cGAS-dependent signaling is acquired during tumorigenesis and that cGAS and DNA-PK activities should be analyzed concertedly to predict the impact of strategies aiming to boost tumor immunogenicity.

cancer biology↗

bioRxiv2021

Usutu virus uses langerin as a receptor to productively infect Langerhans cells more efficiently than West Nile virus.

Usutu virus (USUV) and West Nile virus (WNV) are phylogenetically close emerging arboviruses transmitted by mosquitoes, and constitute a global public health threat. Since USUV and WNV enter the body through the skin, the first immune cells they encounter are skin-resident dendritic cells, the most peripheral outpost of immune defense. This unique network is composed of Langerhans cells (LCs) and dermal DCs, which reside in the epidermis and the dermis, respectively. Using human skin explants, we show that while both viruses can replicate in keratinocytes, they can also infect resident DCs with distinct tropism, since WNV preferentially infects DCs in the dermis, whereas USUV has a greater propensity to infect LCs. Using both purified human epidermal LCs (eLCs) and monocyte derived LCs (MoLCs), we confirm that LCs sustain a faster and more efficient replication of USUV compared with WNV and that this correlates with a more intense innate immune response to USUV compared with WNV. Next, we show that ectopic expression of the LC-specific C-type lectin receptor (CLR), langerin, in HEK293T cells allows WNV and USUV to bind and enter, but supports the subsequent replication of USUV only. Conversely, blocking or silencing langerin in MoLCs or eLCs made them resistant to USUV infection, thus demonstrating that USUV uses langerin to enter and replicate in LCs. Altogether, our results demonstrate that LCs constitute privileged target cells for USUV in human skin, because langerin favors its entry and replication. Intriguingly, this suggests that USUV efficiently escapes the antiviral functions of langerin, which normally safeguards LCs from most viral infections.

microbiology↗