Biology subjects

Lebon, S.

Publications and source records attributed to Lebon, S..

6 recordsLinked to original sources

bioRxiv2026

IL-13 Induces a Tuft Cell-Intrinsic CD45 Checkpoint to Limit Intestinal Type 2 Immunity

Tuft cells initiate intestinal type 2 immunity, yet the mechanisms that restrain excessive tuft cell activation remain poorly understood. Here, we identify the receptor tyrosine phosphatase CD45 (Ptprc), previously considered a hematopoietic marker, as a regulator of intestinal tuft cell function. CD45 expression is restricted to a subset of tuft cells and is induced by helminth infection and IL-13. Epithelial-specific deletion of Ptprc activated a tuft cell inflammatory program, promoted an epithelial inflammatory state, and increased eosinophil accumulation at homeostasis. During Heligmosomoides polygyrus bakeri infection, CD45 deficiency enhanced ILC2 and Th2 responses and reduced parasite burden, demonstrating that epithelial CD45 limits type 2 immunity in vivo. Accordingly, in intestinal organoids, CD45 was dispensable for IL-13-driven tuft cell differentiation but restrained IL-13-responsive transcriptional programs. Mechanistically, CD45-deficient tuft cells exhibited altered protein abundance of STAT5 and IL17RB, implicated in tuft cell immune regulation. Together, these findings identify CD45 as a tuft cell-intrinsic regulatory checkpoint that restrains intestinal type 2 immunity through an IL-13-induced negative-feedback circuit.

immunology↗

bioRxiv2026

Epithelial MHC II antigen presentation dynamically informs intestinal homeostasis and injury

The intestinal epithelium plays a pivotal role in balancing immune tolerance and inflammation, yet how it communicates tissue state to the adaptive immune system remains unclear. Here, we show that intestinal epithelial cells (IECs) encode tissue identity and injury into the major histocompatibility complex class II (MHC II) ligandome. We employed integrated single cell transcriptomics, quantitative proteomics, and high-depth in vivo immunopeptidomics to map the MHC class II self-peptidome of the mouse small intestine across epithelial and immune compartments. Mature enterocytes and intestinal stem cells (ISCs) emerged as the dominant epithelial antigen-presenting cells (APCs), displaying a compartmentalized repertoire of endogenous self-immunopeptides reflecting epithelial differentiation and function. Disruption of epithelial MHC II expression led to loss of antigenic compartmentalization, immune infiltration, extracellular matrix remodeling, and emergence of inflammation-associated immune ligands, demonstrating that epithelial MHC II is required to maintain homeostasis. Functionally, a subset of ISC-derived self-immunopeptides preferentially promotes regulatory CD4{square} T cell responses, linking epithelial antigen presentation and peripheral tolerance. During gut inflammation, the epithelial MHC II landscape shifted toward damage-associated antigens. Together, these findings establish epithelial MHC II presentation as a context-dependent tissue-immune communication system that promotes tolerance in homeostasis and alerts to tissue injury during inflammation.

immunology↗

bioRxiv2025

Oropouche virus infects human neural progenitor cells and alters the growth of brain organoids

Oropouche virus (OROV), is the etiologic agent of Oropouche fever (OROF), an emerging zoonotic disease that has been prevalent in South and Central America since the 1960s. Starting late 2023, the current outbreak has raised concern about vertical transmission and potential adverse pregnancy outcomes. While serological evidences and recent studies support the vertical transmission of OROV, how infection affects the fetal brain remains unclear. Here we show that a strain of OROV, FG_2020, phylogenetically-related to the epidemic strain, efficiently and productively infects human neural progenitor cells and iPSC-derived brain organoids. The main phenotypic effect is proliferation arrest associated with apoptosis leading to the loss of neural rosette organization, a key signature of developing brain architecture. These data indicates that fetal brain is susceptible to OROV infection and that vertical transmission during the first months of pregnancy could lead to pathological effects on brain development.

microbiology↗

bioRxiv2025

Persistent ECM Scarring Reprograms Intestinal Stem Cells to Drive Chronic Inflammation

Tissue regeneration is conventionally viewed as a return to homeostasis. Here, we uncover that the extracellular matrix (ECM) in the colon undergoes a lasting pathological reprogramming following inflammation, forming a remodeled niche--modECM--that persistently disrupts intestinal stem cell (ISC) identity. Using temporal multi-omics, biomechanical profiling, and spatial fate mapping in murine colitis models, we show that modECM, characterized by Collagen XVIII accumulation and immune-driven proteolysis, redirects ISCs toward a wound-associated, squamous-like epithelial state with pro-inflammatory transcriptional signatures. Ex vivo, modECM alone reprograms ISC fate by suppressing Wnt signaling and activating immune recruitment pathways. In vivo, modECM-rich zones sustain T cell infiltration and KRT14 epithelial cell emergence from Lgr5 progenitors. This aberrant epithelial program is mirrored in inflamed rectal biopsies from ulcerative colitis patients. Our findings redefine the ECM as a long-lived instructive compartment that encodes injury memory and promotes maladaptive regeneration, positioning it as a potential therapeutic target in chronic inflammatory disease.

immunology↗

bioRxiv2024

Elucidating early intestinal stem cell response to bacterial infection

Intestinal stem cells (ISCs) are the regenerative force of the gut epithelium. Lgr5+-ISC have been shown to respond to changes in their microenvironment by coping with different metabolites, adapting to caloric changes, and recovering from injury and inflammation. However, how pathogenic bacteria affect adult stem cell regeneration and, as a consequence, the overall tissue adaption to infection has yet to be explored in depth. Here, we interrogated early Lgr5+ ISC responses to an enteric intracellular pathogen by profiling individual IECs from the mouse small intestine. Utilizing GFP-labeled Salmonella enterica, we isolated intracellular invaded cells to elucidate invasion programs of epithelial cell subsets. In particular, we identified a Salmonella-specific infection signature comprised of antimicrobial peptide (AMP) genes, including the Defensin gene family. Our findings demonstrate that Salmonella enterica targets differentiated Paneth, enterocytes, and stem/progenitor cells at these early stages of infection. In response, a rapid Lg5+ ISC-driven cellular remodeling to enterocyte and Paneth lineages expressing AMP genes is initiated to combat the intruders. Importantly, we uncovered an ISC differentiation program via inflammasome activation to protect the crypt environment, while eliminating infected stem cells from the overall stem cell pool. This novel Lgr5+ stem cell defense mechanism not only protects the gut epithelium from persistent bacterial infection but also promotes tissue regeneration. We propose epithelial remodeling to AMP-secreting cells as a novel innate immune response to handle different gut stresses mediated by Lgr5+ ISCs to maintain organizational principles of gut homeostasis and physiology.

immunology↗

bioRxiv2018

Loss of the Wnt/β-catenin pathway in microglia of the developing brain drives pro-inflammatory activation leading to white matter injury

Microglia of the developing brain have unique functional properties but how their activation states is regulated is poorly understood. Inflammatory activation of microglia in the still-developing brain of preterm born infants is associated with permanent neurological sequelae in 9 million infants every year. Investigating the regulators of microglial activation in the developing brain with multiple models of neuroinflammation-mediated injury and primary human microglia we found that a reduction in Wnt/{beta}-catenin signalling is necessary and sufficient to drive an oligodendrocyte-injurious microglial phenotype. We validated in a cohort of preterm born infants that genomic variation in the WNT pathway is associated with the levels of connectivity found in their brains. Using a Wnt agonist delivered by a BBB penetrant microglia-specific targeting nanocarrier we prevented in our animal model the pro-inflammatory microglial activation, white matter injury and behavioural deficits. Collectively, these data validate that the Wnt pathway regulates microglial activation, is critical in the evolution of an important form of human brain injury and is a viable therapeutic target.

immunology↗