Papers by Jacqueline Marvel
Research Square (Research Square), Jul 6, 2023
Adoptive cell transfer between genetically identical hosts is a key tool in the study of the muri... more Adoptive cell transfer between genetically identical hosts is a key tool in the study of the murine immune system. In most models, host and donor differ by a congenic marker, i.e. alleles of a gene coding for a surface protein expressed by immune cells and which allows to trace the donor cells using an epitope specific antibody (Ab). CD45, a glycoprotein expressed by all hematopoietic cells and encoded by the Ptprc gene, constitute one of the main congenic markers used. Its two isoforms, CD45.1 and CD45.2, can be discriminated by flow cytometry using the anti-CD45.1 (clone A20) and anti-CD45.2 (clone 104) Ab. As a consequence, C57BL/6J (B6; CD45.2) and B6.SJL-Ptprc a Pepc b /BoyJ (B6.SJL; CD45.1) mice are widely used in adoptive cell transfer experiments, under the presumption that they differ only at the CD45 (Ptprc) locus. However, the B6.SJL congenic mouse was generated by crossing an SJL mouse with a B6 mouse, followed by serial back-crossing on B6 mice with the selection of CD45.1 expressing animals at each generation. Recent studies identified genetic variations between these congenic strains and highlighted, among other, a differential expression of cathepsin E (CTSE). B6.SJL mouse presents a number of functional differences in hematopoietic stem cell (HSC) engraftmentpotential or immune cell numbers. We show that B6 and B6.SJL mice also differ in their CD8 T cells compartment and CD8 T cells responses to viral infection compared to B6 mouse. We identified Ctse as the most differentially expressed gene between CD8 T cells of B6 and B6.SJL demonstrate that the differences reported between these two mouse strains are not due to CTSE. In order to avoid biases associated with known or unknown polymorphisms found in congenic mice, we used CRISPR/Cas9 genome editing to introduce, in the Ptprc gene of B6 mouse (CD45.2 epitope), the point mutation(s) associated with its transformation into the CD45.1 epitope. We show that only one nucleotide mutation (A904G) leading to an amino acid change (K302E) is sufficient for the protein to be recognized by the anti-CD45.1 Ab. We show that this new B6-Ptprc em(K302E)Jmar /J mouse has similar immune compartment compared to B6 mouse and does not show any difference in HSC engraftment or CD8 antiviral responses. This new strain resolves the experimental biases reported between B6 and B6.SJL mouse lines and should thus represent the new gold standard for adoptive transfer experiments in B6.
bioRxiv (Cold Spring Harbor Laboratory), Feb 10, 2022
In this work, we studied the generation of memory precursor cells following an acute infection by... more In this work, we studied the generation of memory precursor cells following an acute infection by analyzing single-cell RNA-seq data that contained CD8 T cells collected during the postinfection expansion phase. We used different tools to reconstruct the developmental trajectory that CD8 T cells followed after activation. Cells that exhibited a memory precursor signature were identified and positioned on this trajectory. We found that memory precursors are generated continuously with increasing numbers being generated over time. Similarly, expression of genes associated with effector functions was also found to be raised in memory precursors at later time points. The ability of cells to enter quiescence to differentiate into memory cells was confirmed by BrdU pulse-chase experiment in vivo. Analysis of cell counts indicates that the vast majority of memory cells are generated at later time points from cells that have extensively divided.
bioRxiv (Cold Spring Harbor Laboratory), Jun 14, 2019
To develop vaccines it is mandatory yet challenging to account for inter-individual variability d... more To develop vaccines it is mandatory yet challenging to account for inter-individual variability during immune responses. Even in laboratory mice, T cell responses of single individuals exhibit a high heterogeneity that may come from genetic backgrounds, intra-specific processes (e.g. antigen-processing and presentation) and immunization protocols. To account for inter-individual variability in CD8 T cell responses in mice, we propose a dynamical model coupled to a statistical, nonlinear mixed effects model. Average and individual dynamics during a CD8 T cell response are characterized in different immunization contexts (vaccinia virus and tumor). On one hand, we identify biological processes that generate inter-individual variability (activation rate of naive cells, the mortality rate of effector cells, and dynamics of the immunogen). On the other hand, introducing categorical covariates to analyze two different immunization regimens, we highlight the steps of the response impacted by immunogens (priming, differentiation of naive cells, expansion of effector cells and generation of memory cells). The robustness of the model is assessed by confrontation to new experimental data. Our approach allows to investigate immune responses in various immunization contexts, when measurements are scarce or missing, and contributes to a better understanding of inter-individual variability in CD8 T cell immune responses.
bioRxiv (Cold Spring Harbor Laboratory), Jun 12, 2018
Activation of naive CD8 T-cells can lead to the generation of multiple effector and memory subset... more Activation of naive CD8 T-cells can lead to the generation of multiple effector and memory subsets. Multiple parameters associated with activation conditions are involved in generating this diversity that is associated with heterogeneous molecular contents of activated cells. Although naive cell polarisation upon antigenic stimulation and the resulting asymmetric division are known to be a major source of heterogeneity and cell fate regulation, the consequences of stochastic uneven partitioning of molecular content upon subsequent divisions remain unclear yet. Here we aim at studying the impact of uneven partitioning on molecular-content heterogeneity and then on the immune response dynamics at the cellular level. To do so, we introduce a multiscale mathematical model of the CD8 T-cell immune response in the lymph node. In the model, cells are described as agents evolving and interacting in a 2D environment while a set of differential equations, embedded in each cell, models the regulation of intra and extracellular proteins involved in cell differentiation. Based on the analysis of in silico data at the single cell level, we show
Springer eBooks, 1996
Apoptosis or programmed cell death is a cell autonomous suicide pathway characterised by a reduct... more Apoptosis or programmed cell death is a cell autonomous suicide pathway characterised by a reduction in cell volume, chromatin condensation and the activation of an endogenous endonuclease that digest DNA into oligonucleosome length fragments. The cellular machinery necessary for the execution of the death program is present in most cell type in an inactivated form (Raff, 1993) This state of inhibition is dependent on survival signals delivered by exogenous molecules like growth factors or adhesion molecules (Bates, 1994; Harrington, 1994). An increasing number of genes involved in the regulation of apoptosis have been described in the past few years, however the mechanisms responsible for the activation or inactivation of the death program remain poorly understood. The Bcl-2 gene family plays a key role in the regulation of the death program. Over-expression of the Bcl-2 family members such as Bcl-2 or Bcl-XL can inhibit apoptosis induced by removal of survival signals or delivery of a death signal (Oltwai, 1994). To understand the regulation of apoptosis, we would like to identify genes which are involved in the inhibition of apoptosis. These genes could be identified on the basis of homologies with known apoptosis inhibitors or because their product binds to apoptosis regulatory proteins. Alternatively, genes coding for proteins which do not share these properties could be identified by mutagenesis or “random” cDNA expression.
medRxiv (Cold Spring Harbor Laboratory), Mar 12, 2021
Science Translational Medicine, Mar 15, 2023
The diversity of vaccination modalities and infection history are both variables that have an imp... more The diversity of vaccination modalities and infection history are both variables that have an impact on the immune memory of individuals vaccinated against SARS-CoV-2. To gain more accurate knowledge of how these parameters imprint on immune memory, we conducted a long-term follow-up of SARS-CoV-2 spike protein–specific immune memory in unvaccinated and vaccinated COVID-19 convalescent individuals as well as in infection-naïve vaccinated individuals. Here, we report that individuals from the convalescent vaccinated (hybrid immunity) group have the highest concentrations of spike protein–specific antibodies at 6 months after vaccination. As compared with infection-naïve vaccinated individuals, they also display increased frequencies of an atypical mucosa-targeted memory B cell subset. These individuals also exhibited enhanced T H 1 polarization of their SARS-CoV-2 spike protein–specific follicular T helper cell pool. Together, our data suggest that prior SARS-CoV-2 infection increases the titers of SARS-CoV-2 spike protein–specific antibody responses elicited by subsequent vaccination and induces modifications in the composition of the spike protein–specific memory B cell pool that are compatible with enhanced functional protection at mucosal sites.
The Journal of Allergy and Clinical Immunology, Nov 1, 2022
Cellular & Molecular Immunology, May 12, 2020
T cell development proceeds under the influence of a network of transcription factors (TFs). The ... more T cell development proceeds under the influence of a network of transcription factors (TFs). The precise role of Zeb1, a member of this network, remains unclear. Here, we report that Zeb1 expression is induced early during T cell development in CD4 − CD8 − double-negative (DN) stage 2 (DN2). Zeb1 expression was further increased in the CD4 + CD8 + double-positive (DP) stage before decreasing in more mature T cell subsets. We performed an exhaustive characterization of T cells in Cellophane mice that bear Zeb1 hypomorphic mutations. The Zeb1 mutation profoundly affected all thymic subsets, especially DN2 and DP cells. Zeb1 promoted the survival and proliferation of both cell populations in a cell-intrinsic manner. In the periphery of Cellophane mice, the number of conventional T cells was near normal, but invariant NKT cells, NK1.1 + γδ T cells and Ly49 + CD8 T cells were virtually absent. This suggested that Zeb1 regulates the development of unconventional T cell types from DP progenitors. A transcriptomic analysis of WT and Cellophane DP cells revealed that Zeb1 regulated the expression of multiple genes involved in the cell cycle and TCR signaling, which possibly occurred in cooperation with Tcf1 and Heb. Indeed, Cellophane DP cells displayed stronger signaling than WT DP cells upon TCR engagement in terms of the calcium response, phosphorylation events, and expression of early genes. Thus, Zeb1 is a key regulator of the cell cycle and TCR signaling during thymic T cell development. We propose that thymocyte selection is perturbed in Zeb1-mutated mice in a way that does not allow the survival of unconventional T cell subsets.
Journal of Theoretical Biology, Jun 1, 2015
The primary CD8 T cell immune response constitutes a major mechanism to fight an infection by int... more The primary CD8 T cell immune response constitutes a major mechanism to fight an infection by intra-cellular pathogens. We aim at assessing whether pathogen-specific dynamical parameters of the CD8 T cell response can be identified, based on measurements of CD8 T cell counts, using a modeling approach. We generated experimental data consisting in CD8 T cell counts kinetics during the response to three different live intra-cellular pathogens: two viruses (influenza, vaccinia) injected intranasally, and one bacteria (Listeria monocytogenes) injected intravenously. All pathogens harbor the same antigen (NP68), but differ in their interaction with the host. In parallel, we developed a mathematical model describing the evolution of CD8 T cell counts and pathogen amount during an immune response. This model is characterized by 9 parameters and includes relevant feedback controls. The model outputs were compared with the three data series and an exhaustive estimation of the parameter values was performed. By focusing on the ability of the model to fit experimental data and to produce a CD8 T cell population mainly composed of memory cells at the end of the response, critical parameters were identified. We show that a small number of parameters (2 to 4) define the main features of the CD8 T cell immune response and are characteristic of a given pathogen. Among these parameters, two are related to the effector CD8 T cell mediated control of cell and pathogen death. The parameter associated with memory cell death is shown to play no relevant role during the main phases of the CD8 T cell response, yet it becomes essential when looking at the predictions of the model several months after the infection.
Biochemical and Biophysical Research Communications, Jul 1, 1993
Aging Cell, Sep 14, 2018
Hutchinson-Gilford progeria syndrome (HGPS) is a lethal premature aging that recapitulates many n... more Hutchinson-Gilford progeria syndrome (HGPS) is a lethal premature aging that recapitulates many normal aging characteristics. This disorder is caused by mutation in the LMNA gene leading to the production of progerin which induces misshapen nuclei, cellular senescence, and aging. We previously showed that the phospholipase A2 receptor (PLA2R1) promotes senescence induced by replicative, oxidative, and oncogenic stress but its role during progerin-induced senescence and in progeria is currently unknown. Here, we show that knockdown of PLA2R1 prevented senescence induced by progerin expression in human fibroblasts and markedly delayed senescence of HGPS patient-derived fibroblasts. Whole-body knockout of Pla2r1 in a mouse model of progeria decreased some premature aging phenotypes, such as rib fracture and decreased bone content, together with decreased senescence marker. Progerin-expressing human fibroblasts exhibited a high frequency of misshapen nuclei and increased farnesyl diphosphate synthase (FDPS) expression compared to controls; knockdown of PLA2R1 reduced the frequency of misshapen nuclei and normalized FDPS expression. Pamidronate, a FDPS inhibitor, also reduced senescence and misshapen nuclei. Downstream of PLA2R1, we found that p53 mediated the progerin-induced increase in FDPS expression and in misshapen nuclei. These results suggest that PLA2R1 mediates key premature aging phenotypes through a p53/FDPS pathway and might be a new therapeutic target.
SSRN Electronic Journal, 2022
Frontiers in Immunology, 2021
Tissue-resident memory (TRM) CD8+ T-cells play a crucial role in the protection against influenza... more Tissue-resident memory (TRM) CD8+ T-cells play a crucial role in the protection against influenza infection but remain difficult to elicit using recombinant protein vaccines. OVX836 is a recombinant protein vaccine, obtained by the fusion of the DNA sequence of the influenza A nucleoprotein (NP) to the DNA sequence of the OVX313 heptamerization domain. We previously demonstrated that OVX836 provides broad-spectrum protection against influenza viruses. Here, we show that OVX836 intramuscular (IM) immunization induces higher numbers of NP-specific IFNγ-producing CD8+ T-cells in the lung, compared to mutant NP (NPm) and wild-type NP (NPwt), which form monomeric and trimeric structures, respectively. OVX836 induces cytotoxic CD8+ T-cells and high frequencies of lung TRM CD8+ T-cells, while inducing solid protection against lethal influenza virus challenges for at least 90 days. Adoptive transfer experiments demonstrated that protection against diverse influenza subtypes is mediated by N...
Cell Death & Disease, 2021
Although aging is a major risk factor for most types of cancers, it is barely studied in this con... more Although aging is a major risk factor for most types of cancers, it is barely studied in this context. The transmembrane protein PLA2R1 (phospholipase A2 receptor) promotes cellular senescence, which can inhibit oncogene-induced tumor initiation. Functions and mechanisms of action of PLA2R1 during aging are largely unknown. In this study, we observed that old Pla2r1 knockout mice were more prone to spontaneously develop a wide spectrum of tumors compared to control littermates. Consistently, these knockout mice displayed increased Parp1, a master regulator of DNA damage repair, and decreased DNA damage, correlating with large human dataset analysis. Forced PLA2R1 expression in normal human cells decreased PARP1 expression, induced DNA damage and subsequent senescence, while the constitutive expression of PARP1 rescued cells from these PLA2R1-induced effects. Mechanistically, PARP1 expression is repressed by a ROS (reactive oxygen species)-Rb-dependent mechanism upon PLA2R1 expressio...
ObjectivesMultiple Inflammatory Syndrome in Children (MIS-C) is the most severe pediatric form of... more ObjectivesMultiple Inflammatory Syndrome in Children (MIS-C) is the most severe pediatric form of COVID-19 and occurs in previously healthy children. MIS-C combines features of Kawasaki disease and Toxic Shock Syndrome (TSS).MethodsChildren with suspected MIS-C were included within the first week of diagnosis and a large scale immunoassay was performed to determein the immunologic signature of these patients.ResultsWe characterized the immunological profile of 27 MIS-C cases in comparison with 4 KD and 4 TSS cases. Similarly to TSS, an increase of serum inflammatory cytokines (IL-6, TNF-a, CD25s) was observed in MIS-C contrasting with low expression of HLA-DR monocytes, a feature often associated with immune paralysis. Expansions of T cells expressing the Vβ21.3 T cell receptor β chain variable region were detected in both CD4 and CD8 subsets in almost 50% of patients and Vβ21.3-positive T cells expressed high level of HLA-DR highlighting their specific activation. TCR sequencing un...
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Papers by Jacqueline Marvel