Biology subjects

Padonou, F.

Publications and source records attributed to Padonou, F..

4 recordsLinked to original sources

bioRxiv2026

Cross-species chromatin accessibility pinpoints HIVEP3 as a driver of thymic epithelial maturation and self-antigen expression, preventing chronic inflammation

Promiscuous expression of tissue-specific antigens (TSAs) by medullary thymic epithelial cells (mTECs) underpins central T-cell tolerance, relying on NF-{kappa}B-driven mTEC maturation and induction of the autoimmune regulator AIRE. However, a substantial fraction of TSAs is AIRE-independent, implying additional regulators that remain only partially identified. Using cross-species single-cell chromatin accessibility profiling of human and mouse TECs, we find that HIVEP motifs are among the most accessible regulatory elements across the mTEC lineage. Among HIVEP paralogs, HIVEP3 is robustly expressed in mature mTECs across human, mouse and rat; given that rat immunity more closely mirrors human physiology than the mouse, we generated a CRISPR Hivep3-knockout rat line. Hivep3 deletion impairs mTEC maturation, reduces Aire expression and reshapes the TSA repertoire that underlies negative selection and Treg induction, as Hivep3 constrains canonical NF-{kappa}B1 and sustains non-canonical NF-{kappa}B2, the principal mediator of mTEC maturation. Beyond mTECs, Hivep3 deficiency downregulates Foxn1 target genes in cortical TECs and impairs positive selection. In the periphery, Hivep3-KO rats show reduced splenic CD4 T-cells, a shift from naive towards effector-and central-memory phenotypes, increased regulatory T-cells, and a sustained Th1-biased serum profile (elevated IFN-{gamma}, reduced IL-17A) with concurrent systemic metabolic perturbations across all ages. With age, this culminates in chronic inflammation, with multi-organ CD3 T-cell infiltration accompanied by inflammatory lesions. Together, these findings establish HIVEP3 as a previously unrecognised regulator of thymic epithelial function and central tolerance, whose deficiency leads to systemic T-cell-mediated chronic inflammation.

immunology↗

bioRxiv2022

Single-cell profiling identifies clinically relevant interactions between tumor associated macrophages and blood endothelial cells in diffuse large B cell lymphoma

Diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) are the two most common B-cell lymphomas and are characterized by a dynamic crosstalk between tumor B cells and a heterogeneous tumor-supportive microenvironment, including immune, endothelial, and stromal components. Although their impact on the pathogenesis and prognosis of B-cell lymphoma has been acknowledged for years, tumor-associated macrophages (TAM) have not been extensively explored in DLBCL and FL. Herein, we investigate mononuclear phagocytes (MNP) heterogeneity at the single cell level and their potential co-regulation with the stromal and endothelial compartments in B-cell lymphoma lymph nodes compared to reactive secondary lymphoid organs, using a combination of mass cytometry, single cell RNA sequencing, and in silico approaches. We reveal a co-regulation between TAM and blood endothelial cells (BEC) in lymphoma. Moreover, we identify a specific interaction between Annexin A1 (ANXA1)-expressing BEC and formyl-peptide receptors (FPR1/2)-expressing monocytes/macrophages in DLBCL, which we confirm in situ by multiplex immunofluorescence and imaging mass cytometry. This crosstalk is associated to an immunosuppressive tumor microenvironment and an adverse prognosis in DLBCL.

immunology↗

bioRxiv2021

Aire-dependent transcripts escape H3K36me3 and Raver2 induced alternative splicing to sustain central immune tolerance

Aire allows medullary thymic epithelial cells (mTECs) to express and present a large number of self-antigens for central tolerance. Although mTECs express a high diversity of self-antigen splice isoforms, the extent and regulation of alternative splicing events (ASEs) included in their transcripts, notably in those induced by Aire, is unknown. Unexpectedly, and in contrast to Aire-neutral genes, we found that the Aire-sensitive genes exhibit in Aire-positive and negative mTECs, a weak inclusion of ASEs, with about a quarter present in peripheral tissues being excluded from the thymus. We identified Raver2, as a splicing-related factor overrepresented in mTECs and dependent on H3K36me3 marks. We discovered that both Raver2 and methylation of H3K36 promoted ASE inclusion for Aire-neutral genes, leaving Aire-sensitive genes unaffected. Profiling of H3K36me3 revealed its depletion at Aire-sensitive genes, supporting a mechanism, whose setup precedes Aires expression and by which Aire-sensitive genes exhibit weak ASE inclusion through the escape of Raver2s effect. Lack of ASEs in Aire-induced transcripts highlights a role for regulatory T cells in controlling the incomplete Aire-dependent negative selection.

immunology↗

bioRxiv2019

Aire-dependent genes undergo Clp1-mediated 3’UTR shortening associated with higher transcript stability in the thymus

The ability of the immune system to avoid autoimmune disease relies on tolerization of thymocytes to self-antigens whose expression and presentation by thymic medullary epithelial cells (mTECs) is controlled predominantly by Aire at the transcriptional level and possibly regulated at other unrecognized levels. Aire-sensitive gene expression is influenced by several molecular factors, some of which belong to the 3end processing complex, suggesting they might impact transcript stability and levels through an effect on 3UTR shortening. We discovered that Aire-sensitive genes display a pronounced preference for short-3UTR transcript isoforms in mTECs, a feature preceding Aires expression and correlated with the preferential selection of proximal polyA sites by the 3end processing complex. Through an RNAi screen and generation of a lentigenic mouse, we found that one factor, Clp1, promotes 3UTR shortening associated with higher transcript stability and expression of Aire-sensitive genes, revealing a post-transcriptional level of control of Aire-activated expression in mTECs.

genomics↗