Biology subjects

Giraud, M.

Publications and source records attributed to Giraud, M..

11 recordsLinked to original sources

bioRxiv2026

A PATHOGENIC NFKB2 VARIANT CAUSES COMBINED IMMUNODEFICIENCY WITH THYMIC AND PERIPHERAL LYMPHOID DEFECTS IN RATS

The non-canonical NF-kappa B pathway, in which NFKB2 plays a central role, is critical for lymphoid organ development and immune homeostasis. Pathogenic NFKB2 variants have been strongly associated with a broad spectrum of human pathologies, notably immunodysregulation syndromes, characterized by recurrent infections, autoantibody production and endocrine abnormalities. The mechanisms underlying the resulting immune defects remain incompletely understood. In the present study, we characterized the immune phenotype of a novel rat model harboring a Nfkb2 non-sense mutation located in the c-terminal region of the gene (c.2602T>A; p.Tyr867*, Nfkb2p.Tyr867*). This variant has been identified in patients with a familial form of common variable immunodeficiency (CVID) presenting with autoimmunity manifestations. Using this model, we demonstrate that mutated NFKB2 resulted in profound alterations of the thymic microenvironment, including reduced K5+ medullary thymic epithelial cells and decreased AIRE expression, accompanied by altered thymocyte development and impaired thymic regulatory T populations. Peripheral lymphoid organization was also profoundly affected, with absence of lymph nodes, defects in the splenic marginal zone, and alterations of CD4+ and CD8+ T-cell homeostasis, including impaired Treg populations and reduced ICOS expression on CD4+ T cells. The B-cell compartment was markedly altered, with impaired B-cell maturation, characterized by accumulation of IgM+IgD- transitional cells and a marked reduction of IgD+ mature B cells. These abnormalities were associated with impaired humoral immunity and complete absence of circulating immunoglobulins. Collectively, our findings define a systemic combined immunodeficiency phenotype in the Nfkb2-mutated rat, highlighting its utility for studying the role of non-canonical NF-kB signaling in immune system organization and adaptative immunity.

immunology↗

bioRxiv2026

Root Age Structure Governs Long-Term Architecture and Hydraulic Function in Perennial Plants: a Modelling Framework

Background and aims: Perennial root systems develop over decades and exhibit continuous turnover of structural and absorptive components, yet most root architecture models treat woody roots as permanent and neglect root age structure. We developed an empirically constrained modelling framework that explicitly represents age-structured demography, growth regulation and dormancy in perennial root systems. Methods: We extended the functional-structural plant model CPlantBox to simulate perennial root development over decades by integrating age-dependent survival, secondary radial growth and climate-driven dormancy. The model was parameterised using unique three-dimensional root system data from young and mature grapevines, together with dendrochronological root age measurements, and coupled to root hydraulic properties. Key results: Empirical analyses revealed multi-cohort age distributions and substantial turnover of lignified structural roots, contradicting the assumption of a static woody scaffold. The model reproduced age distributions, order-specific survival probabilities and fine-to-structural root length ratios, and generated realistic, genotype-specific three-dimensional architectures. Simulated uptake profiles and hydraulic scenarios showed strong age- and architecture-driven effects. Conclusions: Explicitly representing woody root age distributions and age-dependent processes may fundamentally change predictions of perennial root system architecture and function. The framework advances root modelling beyond annual paradigms and provides a transferable tool for analysing long-term architectural and hydraulic consequences of genotype x climate interactions in perennial crops.

plant biology↗

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↗

bioRxiv2025

Virtual World Coupling with Photosynthesis Evaluation for Synthetic Data Production

In this work, we couple the functional-structural plant model CPlantBox to the Unreal Engine by exploiting the implemented raytracing pipeline to evaluate light influx on the plant surface. There are many approaches for photosynthesis computation and light evaluation, though they typically are limited by versatility, compute speed, or operate on much coarser resolutions. This work specifically addresses the concern that data generation pipelines tend to be unresponsive and do not include model-based knowledge as part of the generation pipeline. Using established photosynthesis solvers, we model the interaction between the Unreal Engine and the FSPM to measure physical properties in the virtual world. This is successful if we are able to reproduce experimental results using an in silico model. As part of the pipeline, we generate a surface geometry and utilize material shaders that are designed to establish a baseline surface model for light interception and transmission, based on simple parameter sets that can be calibrated. Using a Selhausen field experiment as baseline, we reproduce the photosynthesis effectiveness of the plants in the 2016 winter wheat experiments. Our pipeline is deeply intertwined with data generation and has been proven to perform well at scale. In this work, we build on our previous work by showcasing both a simulation study of a light evaluation as well as quantifying how well our system performs on high-performance computing systems.

bioinformatics↗

bioRxiv2024

Root System Architecture Reorganization Under Decreasing Soil Phosphorus Lowers Root System Conductance of Zea mays

The global supply of phosphorus is decreasing. At the same time, climate change reduces the water availability in most regions of the world. Insights on how decreasing phosphorus availability influences plant architecture is crucial to understand its influence on plant functional properties, such as the root systems water uptake capacity. In this study we investigated the structural and functional responses of Zea mays to varying phosphorus fertilization levels focusing especially on the root systems conductance. A rhizotron experiment with soils ranging from severe phosphorus deficiency to sufficiency was conducted. We measured architectural parameters of the whole plant and combined them with root hydraulic properties to simulate time-dependent root system conductance of growing plants under different phosphorus levels. We observed changes of the root system architecture, characterized by decreasing crown root elongation and reduced axial root radii with declining phosphorus availability. Modeling revealed that only plants with optimal phosphorus availability sustained a high root system conductance, while all other phosphorus levels led to a significantly lower root system conductance, both under light and severe phosphorus deficiency. We postulate that phosphorus deficiency initially enhances root system function for drought mitigation but eventually reduce biomass and impairs root development and water uptake in prolonged or severe cases of drought. Our results also highlight the fact that root system organization, rather than its total size, is critical to estimate important root functions.

plant biology↗

bioRxiv2023

Combinatory differentiation of human induced pluripotent stem cells generates thymic epithelium that supports thymic crosstalk and directs dendritic- and CD4/CD8 T-cell full development

The thymus is a primary lymphoid organ playing a crucial role in immune tolerance, by educating thymocytes through a selection mediated by thymic epithelial cells (TEC). Recent advances in gene editing and immunotherapies have made in vitro generation of iPSC-derived T cells a crucial issue with promising therapeutic applications. Current state-of-the-art approaches often fail to accurately replicate the thymic niche, resulting in impaired T cell generation, particularly for CD4+ T cells. Here we address the production of functional mature iPSc-derived TECs that are able to support in vitro T cell generation. We designed a protocol allowing iPSc differentiation into thymic epithelial progenitors (TEP) through an unbiased multifactorial method based on optimal experimental design. Modulation of signaling pathways known to regulate embryonic thymus organogenesis resulted in the obtention of TEPs expressing typical thymic markers. We achieved TEP maturation into medullary and cortical TECs by setting up a hydrogel-based 3D culture supplemented in RANK ligand, resulting in the formation of thymic organoids. To assess the functionality of the generated TECs, primary hematopoietic progenitors were co-cultured in the organoids and showed significantly improved maturation in single-positive CD4 or CD8 T cells. Remarkably, our thymic organoid model shows multilineage differentiation potential, with generation of distinct dendritic cells populations in addition to the T lineages. Thus, generation of functional TECs and thymic organoids offers a practical platform for the study of thymic cellular interactions and paves the road to future cellular therapies by producing mature thymic immune cells of clinical interest.

immunology↗

bioRxiv2023

Development and calibration of the FSPM CPlantBox to represent the interactions between water and carbon fluxes in the soil-plant-atmosphere continuum

A plants development is strongly linked to the water and carbon flows in the soil-plant-atmosphere continuum. Expected climate shifts will alter the water and carbon cycles and will affect plant phenotypes. Comprehensive models which simulate mechanistically and dynamically the feedback loops between a plants three-dimensional development and the water and carbon flows are useful tools to evaluate the sustainability of genotype-environment-management combinations which do not yet exist. In this study, we present the latest version of the open-source three-dimensional Functional-Structural Plant Model CPlantBox with PiafMunch and DuMux coupling. We simulated semi-mechanistically the development of generic C3 monocots from 10 to 25 days after sowing and undergoing an atmospheric dry spell of one week (no precipitation). We compared the results for dry spells starting on different days (day 11 or 18) and with different climates (wetter and colder against drier and warmer atmospheric and initial soil conditions). Compared with the wetter and colder climate, the dry spell with the drier and warmer climate led to a lower instantaneous water use efficiency. Moreover, the lower symplasm turgor for the drier and warmer climate limited the growth, which made the sucrose available for other processes, such as maintenance respiration. Both of these effects were stronger for the later dry spell compared with the early dry spell under the drier and warmer climate. We could thus use CPlantBox to simulate diverging emerging processes (like carbon partitioning) defining the plants phenotypic plasticity response to their environment.

plant biology↗

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↗

bioRxiv2020

Thymocytes trigger self-antigen-controlling pathways in immature medullary thymic epithelial stages

Interactions of developing T cells with Aire+ medullary thymic epithelial cells expressing high levels of MHCII molecules (mTEChi) are critical for the induction of central tolerance. In turn, thymocytes regulate the cellularity of Aire+ mTEChi. However, it remains unknown whether thymocytes control Aire+ mTEChi-precursors that are contained in mTEClo cells or other mTEClo subsets that have recently been delineated or identified by single-cell transcriptomic analyses. Here, using three distinct transgenic mouse models, in which antigen-presentation between mTECs and CD4+ thymocytes is perturbed, we show by high-throughput RNA-seq that self-reactive CD4+ thymocytes induce in mTEClo the expression of tissue-restricted self-antigens, cytokines, chemokines and adhesion molecules important for T-cell development. This gene activation program is combined with a global increase of the active H3K4me3 histone mark. Finally, we show that these interactions induce key mTEC transcriptional regulators and govern mTEClo subset composition, including Aire+ mTEChi-precursors, post-Aire and tuft-like mTECs. Our genome-wide study thus reveals that self-reactive CD4+ thymocytes control multiple unsuspected facets from immature stages of mTECs, which determines their heterogeneity.

immunology↗

bioRxiv2020

Non-permissive human conventional CD1c+ dendritic cells enable trans-infection of human primary renal tubular epithelial cells and protect BK polyomavirus from neutralization

The BK polyomavirus (BKPyV) is a ubiquitous human virus that persists in the renourinary epithelium. Immunosuppression can lead to BKPyV reactivation in the first year post-transplantation in kidney (KTR) and hematopoietic stem cell transplant recipients. In KTR, persistent DNAemia has been correlated to the occurrence of polyomavirus-associated nephropathy (PVAN) that can lead to graft loss if not properly controlled. Based on recent observations that conventional dendritic cells (cDC) specifically infiltrate PVAN lesions, we hypothesized that those cells could play a role in BKPyV infection. We first demonstrated that monocyte-derived DC (MDDC), an in vitro model for mDC, captured BKPyV particles through an unconventional GRAF-1 endocytic pathway. Neither BKPyV particles nor BKPyV-infected cells were shown to activate MDDC. Endocytosed virions were efficiently transmitted to permissive cells and shown to be protected from the antibody-mediated neutralization. Finally, we demonstrated that freshly isolated CD1c+ mDC from the blood and kidney parenchyma behaved similarly to MDDC thus extending our results to cells of clinical relevance. This study sheds light on a potential unprecedented CD1c+ mDC involvement in the BKPyV infection as a promoter of viral spreading.

microbiology↗

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↗