Biology subjects

Lemeille, S.

Publications and source records attributed to Lemeille, S..

3 recordsLinked to original sources

bioRxiv2026

Deciphering auditory neuroprogenitor stemness for large-scale neuronal screening

Sensorineural hearing loss can arise from damage to sensory hair cells, auditory neurons or their synaptic connections, with auditory neuropathy and cochlear synaptopathy highlighting the importance of neural integrity for hearing. The mammalian cochlea has limited capacity to regenerate lost auditory neurons. Understanding the molecular programs that sustain cochlear progenitor expansion and neurogenic competence could support neuronal regeneration and provide renewable models for auditory drug discovery. We previously established that WNT activation combined with dual SMAD inhibition (CHIR-DS) supports scalable expansion and neuronal differentiation of mouse auditory neuroprogenitors (ANPGs). Here, we characterize the transcriptional, chromatin and metabolic changes associated with the induced state. RNA-seq and ATAC-seq identified reduced Id1 and Id2 expression and increased accessibility at proneural basic helix-loop-helix motifs, alongside transcriptional enrichment of translation, mTOR and glucose-metabolism programs. Compared with growth-factor controls, CHIR-DS-treated ANPGs showed slight increase in glycolysis at early passage. However, after long-term expansion, both glycolysis and mitochondrial respiration were markedly enhanced. Human fetal ANPGs also responded to CHIR-DS with increased sphere growth and retained neural differentiation capacity, providing proof of concept beyond the mouse system. Finally, neurons derived from stemness-induced ANPGs (siANs) supported a 384-well reporter assay and a 2,560-compound pilot screen that nominated candidate neurite-outgrowth enhancers. Together, these findings validate the pathway basis of ANPG stemness induction, characterize the resulting molecular and metabolic state, and demonstrate human feasibility and a neuronal screening application.

neuroscience↗

bioRxiv2026

A Glycosylation-Dependent Checkpoint Restrains Intestinal Intra-Epithelial Lymphocyte Activation

Intraepithelial lymphocytes (IELs) are abundant in the intestinal epithelium, where they maintain barrier integrity and provide immune defense. Because of their potent cytotoxic and effector potential, IEL activity must be tightly controlled to prevent tissue damage. However, the mechanisms that calibrate IEL responsiveness remain unclear. Here, we identify glucosaminyl (N-acetyl) transferase 2 (Gcnt2) as a key restrainer of both natural and induced gut IEL. Among T cells, Gcnt2 is uniquely enriched in the intestine and partly dependent on retinoic acid signaling. GCNT2-mediated branched glycosylation marks IELs with signatures of tissue adaptation and reduced TCR responsiveness. Genetic ablation of Gcnt2 enhanced IEL degranulation, cytokine production, and cytotoxicity upon stimulation, improving bacterial clearance and limiting infection-induced disease, while aggravating the pathological consequences of strong T cell activation. Mechanistically, GCNT2-mediated glycosylation of CD45 reduced its phosphatase activity, thereby dampening TCR signaling and effector responses. Together, these findings reveal GCNT2 as a glycosylation-dependent checkpoint that fine-tunes IEL effector functions, uncovering a novel mechanism by which the intestinal immune system balances responsiveness and tolerance. SummaryGCNT2-mediated I-branching glycosylation of CD45 restrains IEL activation.

immunology↗

bioRxiv2024

Interleukin-33 from oligodendrocytes sustains effector differentiation of tissue-resident CD8+ T cells and is a druggable target in CNS autoimmune disease

In chronic inflammatory disorders of the central nervous system (CNS), tissue-resident self-reactive T cells perpetuate disease. The specific tissue factors governing the persistence and continuous differentiation of these cells remain undefined but could represent attractive therapeutic targets. In a model of chronic CNS autoimmunity, we find that oligodendrocyte-derived interleukin-33 (IL-33), an alarmin, is key for locally regulating the pathogenicity of self-reactive CD8+ T cells. The selective ablation of IL-33 from neo-self-antigen-expressing oligodendrocytes mitigates CNS disease. In this context, fewer self-reactive CD8+ T cells persist in the inflamed CNS, and the remaining cells are largely locked into a stem-like precursor program, failing to form TCF-1low effector progeny. Importantly, interventional IL-33 blockade by locally administered somatic gene therapy reduces T cell infiltrates and improves the disease course. Our study identifies oligodendrocyte-derived IL-33 as a druggable tissue factor regulating the differentiation and survival of self-reactive CD8+ T cell in the inflamed CNS. This finding introduces tissue factors as a novel category of immune targets for treating chronic CNS autoimmune diseases.

immunology↗