Biology subjects

Laurent, C.

Publications and source records attributed to Laurent, C..

11 recordsLinked to original sources

bioRxiv2026

Sustained antigenic engagement programs multidimensional CTL states with distinct cytotoxic capacities

Cytotoxic T lymphocytes (CTLs) eliminate infected or malignant cells through repeated target-cell encounters, yet how they sustain cytotoxic activity during extended antigenic stimulation remains poorly understood. In particular, it remains unclear whether preserved population-level killing reflects maintenance of a uniform effector phenotype or diversification into functionally distinct CTL populations. Here, we combined live-cell imaging, high-dimensional cytometry, single-cell RNA sequencing, phenotypic trajectory analysis, population sorting, and rechallenge killing assays to define how human clonal CTLs remodel during sustained antigenic engagement. Prior antigen encounter altered the kinetics and pattern of target-cell membrane permeabilization but did not compromise overall subsequent killing upon rechallenge. Single-cell transcriptomic profiling after prolonged engagement revealed broad remodeling of antigen-experienced CTLs and heterogeneous cytotoxic transcriptional programs. Time-resolved scRNA-seq further showed that these functional dimensions remodeled with distinct kinetics, with rapid induction of activation- and cytotoxicity-associated programs, later remodeling of vesicular-trafficking programs, and progressive reduction of adhesion/ contact interaction -associated programs. High-dimensional cytometry showed that this temporal remodeling was accompanied by progressive redistribution of CTLs across a multidimensional protein-expression landscape defined by distinct combinations of cytotoxic, vesicular/degranulation, activation, cytokine, adhesion, and regulatory features. Phenotypic trajectory analysis organized this protein landscape along a temporal remodeling axis, with early lytic-granule-rich profiles giving way to multiple late-engaged phenotypes with distinct combinations of functional protein features. Surface-marker-defined late CTL populations displayed distinct killing capacities upon rechallenge, demonstrating that preserved population-level cytotoxicity can coexist with substantial functional heterogeneity. Finally, CAR T cells exposed to CD19+ targets retained cytotoxic activity upon rechallenge and acquired multidimensional phenotypic features that partially overlapped with the remodeling framework identified in clonal CTLs. Reanalysis of longitudinal patient-derived CAR T-cell transcriptomes further showed that related functional programs were dynamically organized after infusion, with the features distinguishing responder and non-responder tisa-cel samples changing between the infusion product and day 7. Together, these findings indicate that sustained CTL killing is accompanied by progressive multidimensional remodeling and diversification rather than maintenance of a fixed effector phenotype. Our findings support a model in which population-level cytotoxic activity can be maintained while the CTLs composing that population progressively diversify into functionally distinct states during sustained antigenic engagement.

immunology↗

bioRxiv2025

Dynamics of thalamic directional coding under vestibular imbalance

Head direction cells (HDCs) encode the animals orientation in space and form a core component of the brains navigation system. While their dependence on vestibular input is well established, how directional circuits respond to unilateral vestibular loss (UVL) -- the most frequent and ecologically relevant form of vestibular imbalance -- remains largely unknown. UVL offers a powerful model to investigate how spatial circuits adapt to asymmetric sensory disruption and partial deafferentation. To explore this, we examined the impact of UVL on anterior thalamic nuclei (ATN) activity and spatially tuned neurons in freely moving rats following unilateral vestibular neurectomy (UVN). UVN induced long-lasting alterations in ATN firing dynamics, including reduced theta modulation, diminished burst firing, and selective disruption across functionally defined neuronal classes: head-direction and speed-modulated cells were strongly affected, while angular head velocity and position cells remained largely preserved. Despite initial degradation, HDCs persisted and progressively regained directional tuning. Crucially, spike waveform analysis revealed two distinct HDC subtypes with markedly different vulnerabilities: one subtype showed reduced prevalence and degraded tuning, whereas the other remained resilient and supported the recovery of directional coding. These findings uncover a previously unrecognized heterogeneity within the head direction system and show that compensation following UVL is partial, cell type-specific, and functionally selective. Together, they offer new insight into sensory plasticity within thalamic navigation circuits and provide a framework to understand spatial deficits associated with vestibular imbalance.

neuroscience↗

bioRxiv2025

Trogocytosis-mediated transfer of FOLR2 from Nurse-like cells to CLL cells is linked to their activation and proliferation

Communication with the lymphoid microenvironment is crucial for survival and proliferation of neoplastic B cells in chronic lymphocytic leukemia (CLL). In this study, we examined nurse-like cells (NLCs), CLL-specific macrophages, strongly implicated in CLL pathogenesis, and their interaction with leukemic cells. Using primary patient cells, we demonstrated that NLCs express high levels of folate receptor beta (FOLR2), which correlates with increased survival of cancer cells in vitro. Furthermore, we discovered that CLL cells acquire functional FOLR2 from NLCs via trogocytosis, enhancing their folate uptake. By mimicking the CLL microenvironment with soluble factors, CD40L and IL-15, we observed a strong NLC-dependent CLL cell activation and proliferation. Moreover, we linked this phenomenon with trogocytosis, by demonstrating that FOLR2+ CLL cells are the predominant population of actively cycling cancer cells. By multiplex immunofluorescence analysis of CLL patient lymph nodes, we confirmed the presence of FOLR2 NLCs, and observed their enrichment in more aggressive and proliferative CLL cases. Finally, we detected FOLR2 cancer cells, providing evidence of trogocytosis in situ. Taken together, we propose FOLR2 as a novel marker of protective NLCs, and highlight the importance of trogocytosis in improved CLL cell adaptation, including NLC-mediated activation and proliferation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=58 SRC="FIGDIR/small/630890v3_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1cde6d6org.highwire.dtl.DTLVardef@ee0f67org.highwire.dtl.DTLVardef@1355cb3org.highwire.dtl.DTLVardef@590b29_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOScheme 1.C_FLOATNO Schematic representation of trogocytosis-mediated acquisition of NLC-derived FOLR2 by CLL cells, and its impact on promoting cancer cell adaptability to folate deprivation. 1) CLL cells enter the lymph node (LN) and engage in contact with FOLR2+ NLCs. 2) The presence of T cell- and stromal cell-derived cytokines, CD40L and IL-15 promotes the activation and trogocytosis-mediated acquisition of FOLR2 by CLL cells. 3) FOLR2 trogocytic CLL cells have an advantage in folate acquisition and show increased proliferation compared to the remaining population of cancer cells C_FIG SUMMARYO_LICLL cells acquire functional FOLR2 from NLCs via trogocytosis, a process that is closely linked with enhanced CLL cell activation and proliferation in vitro C_LIO_LIIncreased Frequency of FOLR2 expressing macrophages in more aggressive and proliferative cases of CLL. C_LIO_LIFOLR2 is a marker of M2-like protective NLCs in vitro C_LI

cancer biology↗

bioRxiv2024

Retrosplenial cortex encodes both local and global space in connected environments

In everyday life, mammals navigate through environments composed of multiple interconnected spaces. Understanding how the brain encodes space in such complex settings is essential to uncover the mechanisms that support flexible navigation in the real world. In this study, we investigated how the retrosplenial cortex (RSC) and the hippocampus (HPC) encode spatial information in multi-room environments by recording neuronal activity in rats exploring environments composed of two or four connected rooms. These environments varied both in their structural layout and in their sensory features, allowing us to disentangle the influence of environmental geometry from that of local sensory cues. We found that two types of directional coding coexist within the RSC: classical head direction cells maintained a stable preferred firing direction across all rooms, while multidirectional cells expressed room-specific directional tuning that followed the geometric structure of the environment (e.g., 180{degrees} or 90{degrees} rotations). In addition, non-directional RSC neurons displayed room-specific spatial firing patterns that repeated across rooms following geometric transformations, similar to the activity observed in multidirectional cells. In contrast, hippocampal place cells either remapped between rooms or showed simple translational repetition, without preserving any geometric alignment. Taken together, these findings reveal a functional dissociation between retrosplenial and hippocampal spatial codes. The RSC supports a structured, multi-scale representation of space, segmenting the environment into locally anchored reference frames embedded within a coherent global geometry. The HPC, by contrast, encodes room-specific representations independently for each compartment. This division may support flexible navigation in complex environments by integrating geometry-based spatial segmentation and unification in the RSC with context-specific encoding in the HPC, thereby enabling multi-level spatial coding across interconnected spaces.

neuroscience↗

bioRxiv2023

Microglial adipose triglyceride lipase regulates neuroinflammatory and behavioural responses to LPS

Adipose triglyceride lipase (ATGL), the enzyme that catalyses the rate-limiting step of triglyceride lipolysis, regulates inflammation in peripheral tissues. ATGL has been associated with both pro- and anti-inflammatory responses in different tissues suggesting its actions are dependent on cell type. Recent studies in microglia and macrophages suggest that lipid droplets (LD), a triglyceride storing organelle, and LD lipolysis via ATGL are important components of inflammatory responses. Here, we determined the impact of ATGL inhibition and microglia-specific ATGL loss-of-function on inflammatory and behavioural responses to acute pro-inflammatory insult. First, we evaluated the impact of lipolysis inhibition on lipopolysaccharide (LPS)-induced expression and secretion of cytokines in mouse primary microglia cultures. LPS led to LD accumulation in microglia and altered the expression of lipolysis regulators. The pan-lipase inhibitor ORlistat alleviated LPS-induced expression of IL-1{beta} and IL-6. Specific inhibition of ATGL by ATGListatin had similar anti-inflammatory action on cytokines expression and secretion in both neonatal and adult microglia cultures. Second, targeted and untargeted lipidomic studies revealed that ATGL inhibition reduced LPS-induced generation of pro-inflammatory prostanoids and affected ceramide profile. Finally, the role of ATGL in neuroinflammation was assessed in a novel mouse model with inducible ATGL deletion specifically in microglia. Loss of microglial ATGL in adult male mice dampened LPS-induced expression of IL-6 and reduced LPS-induced sickness behaviour. Together, our results demonstrate that pharmacological inhibition or loss of ATGL-mediated triglyceride lipolysis reduces LPS-induced inflammation to suggest that inhibition of lipolysis plays a beneficial role in neuroinflammation.

neuroscience↗

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↗

bioRxiv2022

Single-cell Spatial Explorer: Easy exploration of spatial and multimodal transcriptomics

The development of single cell technologies yields large datasets of informations as diverse and multimodal as transcriptomes, immunophenotypes, and spatial position from tissue sections in the so-called spatial transcriptomics. Currently however, user-friendly, powerful, and free algorithmic tools for straightforward analysis of spatial transcriptomic datasets are scarce. Here, we introduce Single-Cell Spatial Explorer, an open-source software for multimodal exploration of spatial transcriptomics, examplified with 6 human and murine tissues datasets.

bioinformatics↗

bioRxiv2021

T helper cell-licensed mast cells promote inflammatory Th17 cells

CD4+ T helper cells (Th) infiltrate sites of inflammation and orchestrate the immune response by instructing local leukocytes. Mast cells (MCs) are tissue sentinel cells particularly abundant in skin and mucosa. Here, we analyzed the interplay between human MCs and Th cells and, through the application of RNAseq and functional assays, showed that Th cells induced a specific transcriptomic program in helped MCs (named here MCTH) driving them toward an inflammatory phenotype. The gene signature of MCTH indicated that MCs helped by Th cell acquired in turn the capacity to regulate effector T cell response through wide-range of soluble and membrane ligands. Accordingly, we showed that MCTH promoted Th17 cells and notably an inflammatory subset of Th17, producing both IFN-{gamma} and GM-CSF, through a PGE2 and IL-1{beta} axis. Our findings demonstrate that activated effector/memory CD4+ T cells activate and instruct resting MCs toward a specific differentiated pro-inflammatory phenotype endowed with the capacity to speak back to effector T cells and to mold their functions.

immunology↗

bioRxiv2019

Transactional sex among men who have sex with men participating in the CohMSM prospective cohort study in West Africa

Men who have sex with men (MSM) are at much greater risk of HIV infection in Africa. Little is known about their involvement in transactional sex (TS). We aimed to characterize MSM reporting TS (MSM-TS) and to identify factors associated with their sexual practices using data from the prospective cohort study CohMSM conducted in Burkina Faso, Cote dIvoire, Mali and Togo. Our study focused on HIV-negative MSM, recruited between 06/2015 and 01/2018 by a team of trained peer educators. Scheduled study visits at 6, 12 and 18 months included medical examinations, HIV screening, risk-reduction counselling and face-to-face interviews to collect information on their sociodemographic characteristics, sexual behaviours, and HIV risk-reduction strategies. Three stigmatization sub-scores were constructed. The generalized estimating equation method was used for data analysis. Of the 630 HIV-negative participants recruited at baseline, 463, 410 and 244 had a follow-up visit at 6- and 12- and 18-months, respectively. Over a total of 1747 visits, 478 TS encounters were reported by 289 MSM-TS (45.9%). Of the latter, 91 participants reported systematic TS (31.5%), 55 (19.0 %) stopped reporting TS after baseline, and 53 (18.3%) reported TS after baseline. Ninety participants (31.1 %) reported occasional TS. After adjusting for country of study and follow-up visits, the following factors, reported for the previous 6 months, were associated with a greater likelihood of TS: younger age, an educational level <high-school diploma, satisfaction with current sex life, group sex with men, multiple male sexual partners, condomless anal sex, receptive or versatile anal sex with male sexual partners, giving benefits in exchange for sex with a man, alcohol consumption and drug use during sex, and experiencing stigmatization. The majority of MSM in this study who received benefits in exchange for sex had high-risk HIV infection exposure practices and were characterized by socioeconomic difficulties.

epidemiology↗

bioRxiv2019

Male clients of male sex workers in West Africa: A neglected high risk population

Research on male clients of male sex workers (MCMSW) has been neglected for a long time globally. We aimed to characterize MCMSW and to identify factors associated with their sexual practices using data from the prospective cohort study CohMSM conducted in Burkina Faso, Cote dIvoire, Mali and Togo. Our study focused on HIV-negative men who have sex with other men (MSM) recruited between 06/2015 and 01/2018 by a team of trained peer educators. Scheduled study visits at 6, 12 and 18 months included medical examinations, HIV screening, risk-reduction counselling and face-to-face interviews to collect information on their sociodemographic characteristics, sexual behaviours, and HIV risk-reduction strategies (HIV-RRS). Three stigmatization sub-scores were constructed (experienced, perceived and internalized). Mixed-effects logistic regression was used for data analysis. Of the 280 participants recruited at baseline, 238, 211 and 118, respectively, had a follow-up visit at 6, 12 and 18 months. Over a total of 847 visits, 47 transactional sex (TS) encounters were reported by 38 MCMSW (13.6%). Of the latter, only one participant reported systematic TS (2.6%), 18 (47.4 %) stopped reporting TS after baseline, and 6 (15.8%) reported TS after baseline. Thirteen participants (34.2 %) reported occasional TS. After adjusting for country of study and age, the following self-reported factors were associated with a greater likelihood of being MCMSW: protected anal sex, exclusively insertive anal sex with male sexual partners, avoidance of sex after consuming psychoactive products and experiencing stigmatization (all during the previous 6 months). The majority of MCMSW in this study employed HIV-RRS with male sexual partners, including engaging in protected anal sex, avoidance of sex when consuming psychoactive products, and practising exclusively insertive anal sex.

epidemiology↗

bioRxiv2018

Assessing reliability of intra-tumor heterogeneity estimates from single sample whole exome sequencing data

Tumors are made of evolving and heterogeneous populations of cells which arise from successive appearance and expansion of subclonal populations, following acquisition of mutations conferring them a selective advantage. Those subclonal populations can be sensitive or resistant to different treatments, and provide information about tumor aetiology and future evolution. Hence, it is important to be able to assess the level of heterogeneity of tumors with high reliability for clinical applications.\n\nIn the past few years, a large number of methods have been proposed to estimate intra-tumor heterogeneity from whole exome sequencing (WES) data, but the accuracy and robustness of these methods on real data remains elusive. Here we systematically apply and compare 6 computational methods to estimate tumor heterogeneity on 1,697 WES samples from the cancer genome atlas (TCGA) covering 3 cancer types (breast invasive carcinoma, bladder urothelial carcinoma, and head and neck squamous cell carcinoma), and two distinct input mutation sets. We observe significant differences between the estimates produced by different methods, and identify several likely confounding factors in heterogeneity assessment for the different methods. We further show that the prognostic value of tumor heterogeneity for survival prediction is limited in those datasets, and find no evidence that it improves over prognosis based on other clinical variables.\n\nIn conclusion, heterogeneity inference from WES data on a single sample, and its use in cancer prognosis, should be considered with caution. Other approaches to assess intra-tumoral heterogeneity such as those based on multiple samples may be preferable for clinical applications.

bioinformatics↗