Biology subjects

Gerard, A.

Publications and source records attributed to Gerard, A..

12 recordsLinked to original sources

bioRxiv2026

CXCR3 on transferred T cells enables vaccine-boosted adoptive T-cell therapy in solid tumors

Adoptive T-cell therapy (ACT) has demonstrated marked clinical benefit in hematological malignancies but has limited efficacy against solid tumors. Cancer vaccines can improve ACT, but the mechanisms underlying this combination are poorly understood. Here, we combined ACT with chimpanzee adenovirus ChAdOx1 (ChAd) and modified vaccinia Ankara (MVA) encoding tumor antigens. Whereas PD1 blockade failed to improve ACT, the combination with ChAd/MVA vaccination drove durable regression of established tumors, correlating with expansion of tumor-reactive T cells in lymphoid organs and increased tumor infiltration by T cells. Mechanistically, ChAd priming induced CXCR3 ligands (CXCL10 and CXCL9) in the vaccine-draining lymph node, thereby recruiting transferred T cells to this node independently of cognate antigen. CXCR3 expression on the transferred T cells, but not on host cells, was required for the anti-tumor effect of the combination therapy and favored T-cell accumulation in the vaccine-draining lymph node and the tumor. These findings identify CXCR3 on the transferred T cells as a determinant of ACT plus vaccination synergy and provide a rationale for combining viral-vector vaccines with TCR-T therapies, and for selecting or engineering T cells to retain CXCR3 expression.

immunology↗

bioRxiv2026

Transient immune landscape remodelling shapes CD8 T-cell priming during infection

Immune responses to intracellular pathogens require the generation of a CD8 T-cell response comprised of clones with a broad range of T Cell Receptor (TCR) affinities for their cognate peptide. While high-affinity clones clear pathogens during initial infection, low-affinity T-cells are critical to protect against subsequent encounters with mutated pathogens. Low-affinity T-cells are recruited to an immune response despite known mechanisms that limit their expansion and priming. As such, the mechanism safeguarding the recruitment of low-affinity T-cell clones during infection remains unclear. Here, we show that at the start of an infection, the spatial immune architecture is transiently reorganised to initiate broad T-cell priming. In particular, Tregs become segregated from the initial priming site, resulting in a spatio-temporal window during which pathogen-specific T-cell priming is protected from Treg inhibition. Priming induces the expression of CXCR3 in a TCR affinity-dependent manner, which conditions the retention of activated T-cells in the priming region. Inability to express CXCR3 leads to T-cell relocation towards Treg-rich areas, where their expansion is limited by the lack of the costimulatory molecule CD70. Our study redefines the role of Treg during infection and provides a mechanism to explain how the priming and breadth of the CD8 T-cell response is protected during infection.

immunology↗

bioRxiv2026

The breast tumor microenvironment exploits eosinophil plasticity to suppress their anti-tumor activity

Eosinophils recently emerged as mediators of anti-tumor immunity in immune checkpoint blockade (ICB) treated breast cancer patients. Yet, their role in the treatment-naive breast tumor microenvironment (TME) remains elusive. Here, we show that the breast TME shapes eosinophils into a less active state characterized by loss of Ly6C. While bone marrow and circulating eosinophils are Ly6C, this population progressively transitions into a Ly6C- state marked by reduced cytotoxicity and interferon (IFN) responsiveness during tumor progression. Further investigation of Ly6C uncovered previously unappreciated granularity of eosinophil differentiation in vitro, recapitulating the Ly6C to Ly6C- transition and associated functional loss observed in vivo. IFN stimulation partially restored the Ly6C phenotype ex vivo. Importantly, in ICB-treated tumors, Ly6C+ eosinophils positively correlated with increasing levels of IFNs, suggesting an additional mechanism by which IFNs contribute to effective ICB responses. We propose Ly6C as a key marker of eosinophil differentiation and activation, with the TME shaping eosinophils into a less cytotoxic Ly6C- state.

immunology↗

bioRxiv2025

On the typical development of the central sulcus in infancy: a longitudinal evaluation of its morphology and link to behaviour

IntroductionThe progressive folding of the cortex is an important feature of neurodevelopment starting early during gestation. The central sulcus (CS) is one of the first to fold. Since it represents the anatomical boundary between primary somatosensory and motor functional regions, its developing morphology may inform on the acquisition of sensorimotor skills. We aimed to identify potential asynchronous morphological changes along the CS during infancy, with the hypothesis that this may reflect the gradual emergence of body usage. MethodBased on 3T anatomical magnetic resonance imaging (MRI) and dedicated post-processing, we characterized the evolution in CS depth and curvature in 33 typical infants (aged 1 and 3 months, 22 with longitudinal data) in relation to 23 young adults as a reference. Four regions of interest (ROIs) along the CS, supposed to correspond to different parts of the body and one centred on the hand knob (HK), were reproducibly examined and compared across groups. We also explored the relationship between the age-related changes in morphological features and the global motor scaled scores evaluated at 3 months of age with the Bayley Scales of Infant and Toddler Development. ResultsWhile all ROIs showed significant increases in CS depth and curvature between 3-month-olds and adults, the results were more variable between 1 and 3 months of age depending on cross-sectional and longitudinal analyses. The central-medial and central-lateral regions showed the most consistent increase in depth. Besides, motor development at 3 months of age was not significantly related to CS morphological changes, but a positive trend was observed for depth changes in the (HK-related) central-medial ROI. ConclusionThe rapid evolution of CS folding during infancy may reflect the intense but asynchronous maturation of the brain sensorimotor system, with the differential growth of cortical areas related to body parts and underlying white matter connections. Although it will have to be replicated on larger groups and at other ages, this longitudinal and multimodal study highlights the potential of characterizing CS features as key markers of early sensorimotor development, both at the cerebral and behavioural levels. Combining anatomical and functional neuroimaging could provide deeper insights into the relationship between CS morphology and somatotopic organization in typical infants, but also in infants at risk of developing motor disorders.

neuroscience↗

bioRxiv2025

The 3D affinities of the OT-I TCR to foreign and self-antigens predict their 2D affinities and reveal imperfect antigen discrimination

T cells use the T cell antigen receptor (TCR) to discriminate between higher-affinity foreign and lower-affinity self peptide-MHC (pMHC) antigens. The OT-I mouse TCR is widely used to study anti-gen discrimination utilising many pMHCs, including foreign and self antigens. Previous studies sug-gested that OT-I T cells achieve near-perfect discrimination between higher and lower affinity antigens. Moreover, these 3D affinities measured in solution did not correlate with the 2D membrane affinities, suggesting a complex relationship between 3D and 2D affinities. In contrast, other TCRs have shown imperfect antigen discrimination and strong correlations between 3D and 2D affinities. To resolve these discrepancies, we extended a protocol for measuring ultra-low TCR/pMHC affinities to accurately de-termine the 3D affinities of the OT-I TCR binding 19 pMHC complexes. These revised 3D affinities now strongly correlate with the 2D affinities, and accurately predict functional responses. Importantly, we now find that the OT-I TCR exhibits enhanced yet imperfect antigen discrimination, similar to other TCRs, allowing it to detect abnormally high levels of low-affinity self-antigens. Finally, we show that discrimination is highest with low-affinity pMHC ligands, a finding predicted by the kinetic-proofreading model of antigen discrimination. This work underscores the ability of T cells to effectively gauge prox-ies for 3D affinity within the 2D cell-cell interface, with significant implications for the mechanisms underlying antigen discrimination. Lay abstractT cells protect the body from infection by distinguishing between foreign and self molecules. They do this using a specialized receptor called the T cell receptor (TCR), which senses differences in how strongly it binds to foreign versus self molecules. Scientists have used a mouse TCR called OT-I to understand this process, concluding that OT-I T cells exhibit near perfect discrimination between foreign and self antigens based on a sharp affinity threshold. However, conflicting results from experiments on other TCRs hinted at a more complicated picture. In this study, we used an improved method to accurately measure OT-I TCR binding affinity to 19 peptides, including foreign and self antigens. In contrast to previous results and like other TCRs, we found that OT-I T cells display enhanced but im-perfect discrimination, enabling them to be activated by high levels of self antigen. The new data also revealed that the ability of T cells to discriminate antigens is particularly high at low affinities. These findings reconcile apparent discrepancies between the OT-I TCR and other TCRs, and have implications for understanding diseases where T cells often respond to self antigen, such as autoimmunity and cancer. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=149 SRC="FIGDIR/small/632665v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@977df5org.highwire.dtl.DTLVardef@1ce7bd3org.highwire.dtl.DTLVardef@12363cdorg.highwire.dtl.DTLVardef@6d5573_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Autoantigen TRIM21 (Ro52) assembles pro-inflammatory immune complexes following lytic cell death

Sjogrens disease (SjD) causes localised and systemic inflammation due to autoantibody production against intracellular proteins, such as TRIM21/Ro52. TRIM21 is an E3 ubiquitin ligase which binds antibody Fc domains on opsonised pathogens, which have escaped extracellular immunity and entered cytosols; TRIM21 ubiquitinates these, driving their proteasomal degradation. How and why TRIM21 becomes an autoantigen remains unclear. We show that TRIM21 is released upon lytic cell death (pyroptosis/necroptosis) but not apoptosis. Released TRIM21 binds circulating antibody Fc domains, and forms large immune complexes (ICs). These are further enhanced with TRIM21/Ro52 seropositive SjD plasma antibodies, where interactions are mediated via both Fc and F(ab)2 domains. TRIM21-ICs are taken up by macrophages, which in high interferon environments drive pro-inflammatory responses, antigen presentation, and inflammatory and metabolic transcriptional changes. Whilst many cytosolic proteins are released by dead cells, due to its high affinity for antibodies, TRIM21 can generate large ICs. This may perpetuate inflammation and antigen presentation, causing TRIM21 to be highly autoimmunogenic. One Sentence SummaryHow the intracellular protein TRIM21 becomes an autoantigen.

immunology↗

bioRxiv2024

IFNgamma-dependent remodelling of the myeloid landscape underlies control of IFNgamma-insensitive tumours

Loss of IFN{gamma}-sensitivity by tumours is thought to be a mechanism enabling evasion, as some cancers lacking IFN{gamma}-signalling demonstrate resistance to checkpoint immunotherapy. However, recent studies demonstrated that IFN{gamma}-resistant tumours are well-controlled and sensitized for immunotherapy. The underlying mechanism leading to enhanced immune responses in those patients is unknown. Using IFN{gamma}-insensitive melanoma tumours which were well-controlled by the endogenous anti-tumour response, we found that despite low basal MHC class I expression by tumours, CD8+ T cell infiltration was not hindered and, unexpectedly, their production of IFN{gamma} was still important for tumour control. Mechanistically, IFN{gamma} triggers pro-inflammatory remodelling of IFN{gamma}-insensitive tumours, affecting the differentiation of myeloid cells. Predominantly, immunosuppressive macrophages are inhibited, while inflammatory phenotypes of monocytes and mono-macs are preserved in IFN{gamma}-insensitive tumours. This is supported by a co-dependency between CD8+ T cells and monocyte/macrophages, as depletion of one resulted in loss of the other. Our work demonstrates an important mechanistic understanding of how IFN{gamma} resistance does not preclude failure of anti-tumour responses. Importantly, immune remodelling appears to be dominant in IFN{gamma}-sensitive and IFN{gamma}-insensitive mixed tumours, and is enriched in humans with tumours mutated in the IFN{gamma} pathway, suggesting this may be leveraged for therapy in the future.

immunology↗

bioRxiv2023

Paracetamol/acetaminophen hepatotoxicity: new markers for monitoring the elimination of the reactive N-Acetyl-p-benzoquinone imine

Paracetamol/acetaminophen (N-acetyl-p-aminophenol, APAP) overdose is one of the most important causes of drug-induced liver injury worldwide. Hepatotoxicity induced by APAP is mainly caused by the production of N-acetyl-p-benzoquinone imine (NAPQI), a highly reactive intermediate formed predominantly via the cytochrome P450 2E1. Here, we used human studies and in vitro models to demonstrate that NAPQI-derived thiomethyl metabolites identified using high-resolution mass spectrometry could serve to monitor NAPQI detoxification and elimination in patients (after intake at recommended dose or after intoxication), and to study inter-individual variability in NAPQI production. Using in vitro human models, we showed that these thiomethyl metabolites are directly linked to NAPQI detoxification since they are mainly formed after exposure to glutathione-derived conjugates via an overlooked pathway called the thiomethyl shunt. These long-term thiomethyl metabolites have great potential in future clinical studies in order to provide a more reliable history of APAP ingestion in case of acute intoxication or to study underlying causes involved in APAP-induced hepatotoxicity. One Sentence SummaryThiomethyl metabolites are new markers to monitor the elimination of the toxic N-acetyl-p-benzoquinone imine after therapeutic use or intoxication.

pharmacology and toxicology↗

bioRxiv2023

Integration of Avidity and Differentiation is enabled by CD8+ T-cell sensing of IFN-γ

The most effective responses to intracellular pathogens have a breadth of T-cell clones with different affinities for their cognate peptide, and a diversity of functional phenotypes, from effector to long-lived memory cells. While high- and low-affinity T-cells are inherently skewed towards becoming effector and memory, respectively, overall, both functional subsets exploit a wide range of affinities. How the breadth of affinities and functionalities are coordinated is therefore unclear. In this study, we provide evidence that direct sensing of the cytokine IFN-{gamma} by CD8+ T-cells is a factor controlling the integration of T-cell affinity and differentiation during infection. IFN-{gamma} increases the expansion of low-affinity T-cells, allowing them to overcome the selective advantage of high-affinity T-cells. Concomitantly, IFN-{gamma} reinforces high-affinity T-cell entry into the memory pool. As a result, direct IFN-{gamma} sensing by CD8+ T-cells increases the avidity of the memory response. This comes at the expense of the primary T-cell response, for which IFN-{gamma} decreases the avidity, leading to sub-optimum immunity to infection. IFN-{gamma} sensing by CD8+ T-cells is paracrine, provided by a distinct subset of CD8+ T-cells called Virtual Memory T-cells, an antigen inexperienced subset that harbors memory features. Overall, we propose that IFN-{gamma} and Virtual Memory T-cells fulfil a critical immunoregulatory role by enabling the coordination of T-cell avidity and fate.

immunology↗

bioRxiv2022

The DeepFaune initiative: a collaborative effort towards the automatic identification of the French fauna in camera-trap images

Camera traps have revolutionized how ecologists monitor wildlife, but their full potential is realized only when the hundreds of thousands of collected images can be readily classified with minimal human intervention. Deep-learning classification models have allowed extraordinary progress towards this end, but trained models remain rare and are only now emerging for European fauna. We report on the first milestone of the DeepFaune initiative (https://www.deepfaune.cnrs.fr), a large-scale collaboration between more than 50 partners involved in wildlife research, conservation and management in France. We developed a classification model trained to recognize 26 species or higher-level taxa. The classification model achieved 0.97 validation accuracy and often >0.95 precision and recall for many classes. These performances were generally higher than 0.90 when tested on independent out-of-sample datasets for which we used image redundancy contained in sequence of images. We implemented our model in a software to classify images stored locally on a personal computer, so as to provide a free, user-friendly and high-performance tool for wildlife practitioners to automatically classify camera-trap images.

ecology↗

bioRxiv2021

Drosophila functional screening of de novo variants in autism uncovers deleterious variants and facilitates discovery of rare neurodevelopmental diseases

Individuals with autism spectrum disorders (ASD) exhibit an increased burden of de novo variants in a broadening range of genes. We functionally tested the effects of ASD missense variants using Drosophila through humanization rescue and overexpression-based strategies. We studied 79 ASD variants in 74 genes identified in the Simons Simplex Collection and found 38% of them caused functional alterations. Moreover, we identified GLRA2 as the cause of a spectrum of neurodevelopmental phenotypes beyond ASD in eight previously undiagnosed subjects. Functional characterization of variants in ASD candidate genes point to conserved neurobiological mechanisms and facilitates gene discovery for rare neurodevelopmental diseases.

genetics↗

bioRxiv2020

Multi- and transgenerational disruption of maternal behavior and female puberty by Endocrine Disrupting Chemical (EDC) mixture exposure

Female reproductive development and maternal behavior are two intertwined phenotypes centrally controlled by the hypothalamus. Endocrine disrupting chemicals (EDC) can alter these processes especially when animals are exposed during development. We propose the concept that developmental exposure to a low environmentally relevant dose of EDC mixture induces a transgenerational alteration of female rat pubertal timing and ovarian physiology throughout epigenetic reprograming of hypothalamic Kiss1, Esr1 and Oxt1 loci. Such exposure also caused a multigenerational reduction of maternal behavior induced by the loss in hypothalamic dopaminergic signaling. Our results identify the hypothalamic Polycomb Group of epigenetic repressors as actors of this mechanism of transgenerational reproductive disruption. Using a cross-fostering approach, we identified that while the reduction in maternal phenotype was normalized in EDC exposed pups raised by unexposed dams, no reversal of the pubertal phenotype was achieved, suggesting a germline transmission of the reproductive phenotype.

neuroscience↗