Publications by authors named "Sébastien Jaeger"

19 Publications

  • Page 1 of 1

TCR and CD28 Concomitant Stimulation Elicits a Distinctive Calcium Response in Naive T Cells.

Front Immunol 2018 4;9:2864. Epub 2018 Dec 4.

Aix Marseille University, CNRS, INSERM, CIML, Marseille, France.

T cell activation is initiated upon ligand engagement of the T cell receptor (TCR) and costimulatory receptors. The CD28 molecule acts as a major costimulatory receptor in promoting full activation of naive T cells. However, despite extensive studies, why naive T cell activation requires concurrent stimulation of both the TCR and costimulatory receptors remains poorly understood. Here, we explore this issue by analyzing calcium response as a key early signaling event to elicit T cell activation. Experiments using mouse naive CD4 T cells showed that engagement of the TCR or CD28 with the respective cognate ligand was able to trigger a rise in fluctuating calcium mobilization levels, as shown by the frequency and average response magnitude of the reacting cells compared with basal levels occurred in unstimulated cells. The engagement of both TCR and CD28 enabled a further increase of these two metrics. However, such increases did not sufficiently explain the importance of the CD28 pathways to the functionally relevant calcium responses in T cell activation. Through the autocorrelation analysis of calcium time series data, we found that combined but not separate TCR and CD28 stimulation significantly prolonged the average decay time (τ) of the calcium signal amplitudes determined with the autocorrelation function, compared with its value in unstimulated cells. This increasement of decay time (τ) uniquely characterizes the fluctuating calcium response triggered by concurrent stimulation of TCR and CD28, as it could not be achieved with either stronger TCR stimuli or by co-engaging both TCR and LFA-1, and likely represents an important feature of competent early signaling to provoke efficient T cell activation. Our work has thus provided new insights into the interplay between the TCR and CD28 early signaling pathways critical to trigger naive T cell activation.
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http://dx.doi.org/10.3389/fimmu.2018.02864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288997PMC
October 2019

High-Dimensional Single-Cell Analysis Identifies Organ-Specific Signatures and Conserved NK Cell Subsets in Humans and Mice.

Immunity 2018 11 6;49(5):971-986.e5. Epub 2018 Nov 6.

Aix Marseille Univ, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, Marseille, France; Immunology, Marseille Immunopole, Hôpital de la Timone, Assistance Publique des Hôpitaux de Marseille, France; Innate Pharma Research Laboratories, Innate Pharma, Marseille, France. Electronic address:

Natural killer (NK) cells are innate lymphoid cells (ILCs) involved in antimicrobial and antitumoral responses. Several NK cell subsets have been reported in humans and mice, but their heterogeneity across organs and species remains poorly characterized. We assessed the diversity of human and mouse NK cells by single-cell RNA sequencing on thousands of individual cells isolated from spleen and blood. Unbiased transcriptional clustering revealed two distinct signatures differentiating between splenic and blood NK cells. This analysis at single-cell resolution identified three subpopulations in mouse spleen and four in human spleen, and two subsets each in mouse and human blood. A comparison of transcriptomic profiles within and between species highlighted the similarity of the two major subsets, NK1 and NK2, across organs and species. This unbiased approach provides insight into the biology of NK cells and establishes a rationale for the translation of mouse studies to human physiology and disease.
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http://dx.doi.org/10.1016/j.immuni.2018.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269138PMC
November 2018

Detection of long-range electrostatic interactions between charged molecules by means of fluorescence correlation spectroscopy.

Phys Rev E 2017 Aug 9;96(2-1):022403. Epub 2017 Aug 9.

CNRS Centre de Physique Théorique UMR7332, 13288 Marseille, France.

In the present paper, an experimental feasibility study on the detection of long-range intermolecular interactions through three-dimensional molecular diffusion in solution is performed. This follows recent theoretical and numerical analyses reporting that long-range electrodynamic forces between biomolecules could be identified through deviations from Brownian diffusion. The suggested experimental technique was fluorescence correlation spectroscopy (FCS). By considering two oppositely charged molecular species in aqueous solution, namely, lysozymes and fluorescent dye molecules (Alexa488), the diffusion coefficient of the dyes has been measured for different values of the concentration of lysozyme, that is, for different average distances between the oppositely charged molecules. For our model, long-range interactions are of electrostatic origin, suggesting that their action radius can be varied by changing the ionic strength of the solution. The experimental outcomes clearly prove the detectability of long-range intermolecular interactions by means of the FCS technique. Molecular dynamics simulations provide a clear and unambiguous interpretation of the experimental results.
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http://dx.doi.org/10.1103/PhysRevE.96.022403DOI Listing
August 2017

RSAT matrix-clustering: dynamic exploration and redundancy reduction of transcription factor binding motif collections.

Nucleic Acids Res 2017 Jul;45(13):e119

Aix Marseille Univ, INSERM, TAGC, Theory and Approaches of Genomic Complexity, UMR_S 1090, Marseille, France.

Transcription factor (TF) databases contain multitudes of binding motifs (TFBMs) from various sources, from which non-redundant collections are derived by manual curation. The advent of high-throughput methods stimulated the production of novel collections with increasing numbers of motifs. Meta-databases, built by merging these collections, contain redundant versions, because available tools are not suited to automatically identify and explore biologically relevant clusters among thousands of motifs. Motif discovery from genome-scale data sets (e.g. ChIP-seq) also produces redundant motifs, hampering the interpretation of results. We present matrix-clustering, a versatile tool that clusters similar TFBMs into multiple trees, and automatically creates non-redundant TFBM collections. A feature unique to matrix-clustering is its dynamic visualisation of aligned TFBMs, and its capability to simultaneously treat multiple collections from various sources. We demonstrate that matrix-clustering considerably simplifies the interpretation of combined results from multiple motif discovery tools, and highlights biologically relevant variations of similar motifs. We also ran a large-scale application to cluster ∼11 000 motifs from 24 entire databases, showing that matrix-clustering correctly groups motifs belonging to the same TF families, and drastically reduced motif redundancy. matrix-clustering is integrated within the RSAT suite (http://rsat.eu/), accessible through a user-friendly web interface or command-line for its integration in pipelines.
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http://dx.doi.org/10.1093/nar/gkx314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737723PMC
July 2017

Protein synthesis inhibition and GADD34 control IFN-β heterogeneous expression in response to dsRNA.

EMBO J 2017 03 18;36(6):761-782. Epub 2017 Jan 18.

CNRS, INSERM, CIML, Aix Marseille University, Marseille, France

In innate immune responses, induction of type-I interferons (IFNs) prevents virus spreading while viral replication is delayed by protein synthesis inhibition. We asked how cells perform these apparently contradictory activities. Using single fibroblast monitoring by flow cytometry and mathematical modeling, we demonstrate that type-I IFN production is linked to cell's ability to enter dsRNA-activated PKR-dependent translational arrest and then overcome this inhibition by decreasing eIF2α phosphorylation through phosphatase 1c cofactor GADD34 (Ppp1r15a) expression. GADD34 expression, shown here to be dependent on the IRF3 transcription factor, is responsible for a biochemical cycle permitting pulse of IFN synthesis to occur in cells undergoing protein synthesis inhibition. Translation arrest is further demonstrated to be key for anti-viral response by acting synergistically with MAVS activation to amplify TBK1 signaling and IFN-β mRNA transcription, while GADD34-dependent protein synthesis recovery contributes to the heterogeneous expression of IFN observed in dsRNA-activated cells.
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http://dx.doi.org/10.15252/embj.201695000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5350567PMC
March 2017

Long-Range Control of V(D)J Recombination & Allelic Exclusion: Modeling Views.

Adv Immunol 2015 19;128:363-413. Epub 2015 Sep 19.

Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université UM2, Inserm, U1104, CNRS UMR7280, 13288 Marseille, France. Electronic address:

Allelic exclusion of immunoglobulin (Ig) and T-cell receptor (TCR) genes ensures the development of B and T lymphocytes operating under the mode of clonal selection. This phenomenon associates asynchronous V(D)J recombination events at Ig or TCR alleles and inhibitory feedback control. Despite years of intense research, however, the mechanisms that sustain asymmetric choice in random Ig/TCR dual allele usage and the production of Ig/TCR monoallelic expressing B and T lymphocytes remain unclear and open for debate. In this chapter, we first recapitulate the biological evidence that almost from the start appeared to link V(D)J recombination and allelic exclusion. We review the theoretical models previously proposed to explain this connection. Finally, we introduce our own mathematical modeling views based on how the developmental dynamics of individual lymphoid cells combine to sustain allelic exclusion.
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http://dx.doi.org/10.1016/bs.ai.2015.08.002DOI Listing
February 2016

RSAT 2015: Regulatory Sequence Analysis Tools.

Nucleic Acids Res 2015 Jul 22;43(W1):W50-6. Epub 2015 Apr 22.

European Genomic Institute for Diabetes (EGID), F-3508, 59000 Lille, France Laboratoire de Bioinformatique des Génomes et des Réseaux (BiGRe), Université Libre de Bruxelles, Campus Plaine, CP 263, Bld du Triomphe, B-1050 Bruxelles, Belgium

RSAT (Regulatory Sequence Analysis Tools) is a modular software suite for the analysis of cis-regulatory elements in genome sequences. Its main applications are (i) motif discovery, appropriate to genome-wide data sets like ChIP-seq, (ii) transcription factor binding motif analysis (quality assessment, comparisons and clustering), (iii) comparative genomics and (iv) analysis of regulatory variations. Nine new programs have been added to the 43 described in the 2011 NAR Web Software Issue, including a tool to extract sequences from a list of coordinates (fetch-sequences from UCSC), novel programs dedicated to the analysis of regulatory variants from GWAS or population genomics (retrieve-variation-seq and variation-scan), a program to cluster motifs and visualize the similarities as trees (matrix-clustering). To deal with the drastic increase of sequenced genomes, RSAT public sites have been reorganized into taxon-specific servers. The suite is well-documented with tutorials and published protocols. The software suite is available through Web sites, SOAP/WSDL Web services, virtual machines and stand-alone programs at http://www.rsat.eu/.
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http://dx.doi.org/10.1093/nar/gkv362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489296PMC
July 2015

Site- and allele-specific polycomb dysregulation in T-cell leukaemia.

Nat Commun 2015 Jan 23;6:6094. Epub 2015 Jan 23.

1] Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288 Marseille, France [2] INSERM U1104, 13288 Marseille, France [3] CNRS UMR7280, 13288 Marseille, France.

T-cell acute lymphoblastic leukaemias (T-ALL) are aggressive malignant proliferations characterized by high relapse rates and great genetic heterogeneity. TAL1 is amongst the most frequently deregulated oncogenes. Yet, over half of the TAL1(+) cases lack TAL1 lesions, suggesting unrecognized (epi)genetic deregulation mechanisms. Here we show that TAL1 is normally silenced in the T-cell lineage, and that the polycomb H3K27me3-repressive mark is focally diminished in TAL1(+) T-ALLs. Sequencing reveals that >20% of monoallelic TAL1(+) patients without previously known alterations display microinsertions or RAG1/2-mediated episomal reintegration in a single site 5' to TAL1. Using 'allelic-ChIP' and CrispR assays, we demonstrate that such insertions induce a selective switch from H3K27me3 to H3K27ac at the inserted but not the germline allele. We also show that, despite a considerable mechanistic diversity, the mode of oncogenic TAL1 activation, rather than expression levels, impact on clinical outcome. Altogether, these studies establish site-specific epigenetic desilencing as a mechanism of oncogenic activation.
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http://dx.doi.org/10.1038/ncomms7094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317503PMC
January 2015

Experimental detection of long-distance interactions between biomolecules through their diffusion behavior: numerical study.

Phys Rev E Stat Nonlin Soft Matter Phys 2014 Aug 6;90(2):022703. Epub 2014 Aug 6.

CNRS Centre de Physique Théorique UMR7332, 13288 Marseille, France and Aix-Marseille University, Marseille, France.

The dynamical properties and diffusive behavior of a collection of mutually interacting particles are numerically investigated for two types of long-range interparticle interactions: Coulomb-electrostatic and dipole-electrodynamic. It is shown that when the particles are uniformly distributed throughout the accessible space, the self-diffusion coefficient is always lowered by the considered interparticle interactions, irrespective of their attractive or repulsive character. This fact is also confirmed by a simple model to compute the correction to the Brownian diffusion coefficient due to the interactions among the particles. These interactions are also responsible for the onset of dynamical chaos and an associated chaotic diffusion which still follows an Einstein-Fick-like law for the mean-square displacement as a function of time. Transitional phenomena are observed for Coulomb-electrostatic (repulsive) and dipole-electrodynamic (attractive) interactions considered both separately and in competition. The outcomes reported in this paper clearly indicate a feasible experimental method to probe the activation of resonant electrodynamic interactions among biomolecules.
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http://dx.doi.org/10.1103/PhysRevE.90.022703DOI Listing
August 2014

The speed of change: towards a discontinuity theory of immunity?

Nat Rev Immunol 2013 10 2;13(10):764-9. Epub 2013 Sep 2.

Université Paris-Sorbonne, Philosophy Department, 1 rue Victor Cousin, 75005 Paris, France.

Immunology - though deeply experimental in everyday practice - is also a theoretical discipline. Recent advances in the understanding of innate immunity, how it is triggered and how it shares features that have previously been uniquely ascribed to the adaptive immune system, can contribute to the refinement of the theoretical framework of immunology. In particular, natural killer cells and macrophages are activated by transient modifications, but adapt to long-lasting modifications that occur in the surrounding tissue environment. This process facilitates the maintenance of self-tolerance while permitting efficient immune responses. In this Essay we extend this idea to other components of the immune system and we propose some general principles that lay the foundations for a unifying theory of immunity - the discontinuity theory. According to this theoretical framework, effector immune responses (namely, activated responses that lead to the potential elimination of the target antigen) are induced by an antigenic discontinuity; that is, by the sudden modification of molecular motifs with which immune cells interact.
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http://dx.doi.org/10.1038/nri3521DOI Listing
October 2013

Epigenetic aspects of lymphocyte antigen receptor gene rearrangement or 'when stochasticity completes randomness'.

Immunology 2013 Jun;139(2):141-50

Centre d'Immunologie de Marseille-Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (Inserm) U1104, Centre National de la Recherche Scientifique (CNRS)UMR7280, Aix-Marseille University UM2, Marseille, France.

To perform their specific functional role, B and T lymphocytes, cells of the adaptive immune system of jawed vertebrates, need to express one (and, preferably, only one) form of antigen receptor, i.e. the immunoglobulin or T-cell receptor (TCR), respectively. This end goal depends initially on a series of DNA cis-rearrangement events between randomly chosen units from separate clusters of V, D (at some immunoglobulin and TCR loci) and J gene segments, a biomolecular process collectively referred to as V(D)J recombination. V(D)J recombination takes place in immature T and B cells and relies on the so-called RAG nuclease, a site-specific DNA cleavage apparatus that corresponds to the lymphoid-specific moiety of the VDJ recombinase. At the genome level, this recombinase's mission presents substantial biochemical challenges. These relate to the huge distance between (some of) the gene segments that it eventually rearranges and the need to achieve cell-lineage-restricted and developmentally ordered routines with at times, mono-allelic versus bi-allelic discrimination. The entire process must be completed without any recombination errors, instigators of chromosome instability, translocation and, potentially, tumorigenesis. As expected, such a precisely choreographed and yet potentially risky process demands sophisticated controls; epigenetics demonstrates what is possible when calling upon its many facets. In this vignette, we will recall the evidence that almost from the start appeared to link the two topics, V(D)J recombination and epigenetics, before reviewing the latest advances in our knowledge of this joint venture.
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http://dx.doi.org/10.1111/imm.12057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3647179PMC
June 2013

Assessing the efficiency and significance of Methylated DNA Immunoprecipitation (MeDIP) assays in using in vitro methylated genomic DNA.

BMC Res Notes 2010 Sep 16;3:240. Epub 2010 Sep 16.

Centre d'Immunologie de Marseille-Luminy, Université Aix Marseille, Marseille, France.

Background: DNA methylation contributes to the regulation of gene expression during development and cellular differentiation. The recently developed Methylated DNA ImmunoPrecipitation (MeDIP) assay allows a comprehensive analysis of this epigenetic mark at the genomic level in normal and disease-derived cells. However, estimating the efficiency of the MeDIP technique is difficult without previous knowledge of the methylation status of a given cell population. Attempts to circumvent this problem have involved the use of in vitro methylated DNA in parallel to the investigated samples. Taking advantage of this stratagem, we sought to improve the sensitivity of the approach and to assess potential biases resulting from DNA amplification and hybridization procedures using MeDIP samples.

Findings: We performed MeDIP assays using in vitro methylated DNA, with or without previous DNA amplification, and hybridization to a human promoter array. We observed that CpG content at gene promoters indeed correlates strongly with the MeDIP signal obtained using in vitro methylated DNA, even when lowering significantly the amount of starting material. In analyzing MeDIP products that were subjected to whole genome amplification (WGA), we also revealed a strong bias against CpG-rich promoters during this amplification procedure, which may potentially affect the significance of the resulting data.

Conclusion: We illustrate the use of in vitro methylated DNA to assess the efficiency and accuracy of MeDIP procedures. We report that efficient and reproducible genome-wide data can be obtained via MeDIP experiments using relatively low amount of starting genomic DNA; and emphasize for the precaution that must be taken in data analysis when an additional DNA amplification step is required.
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http://dx.doi.org/10.1186/1756-0500-3-240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2949662PMC
September 2010

TCR beta allelic exclusion in dynamical models of V(D)J recombination based on allele independence.

J Immunol 2010 Aug 28;185(3):1622-32. Epub 2010 Jun 28.

Centre de Physique Théorique, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6207, Université de la Méditerranée-Université de Provence-Université Sud Toulon Var, Centre National de la Recherche Scientifique Luminy Case 907, France.

Allelic exclusion represents a major aspect of TCRbeta gene assembly by V(D)J recombination in developing T lymphocytes. Despite recent progress, its comprehension remains problematic when confronted with experimental data. Existing models fall short in terms of incorporating into a unique distribution all the cell subsets emerging from the TCRbeta assembly process. To revise this issue, we propose dynamical, continuous-time Markov chain-based modeling whereby essential steps in the biological procedure (D-J and V-DJ rearrangements and feedback inhibition) evolve independently on the two TCRbeta alleles in every single cell while displaying random modes of initiation and duration. By selecting parameters via fitting procedures, we demonstrate the capacity of the model to offer accurate fractions of all distinct TCRbeta genotypes observed in studies using developing and mature T cells from wild-type or mutant mice. Selected parameters in turn afford relative duration for each given step, hence updating TCRbeta recombination distinctive timings. Overall, our dynamical modeling integrating allele independence and noise in recombination and feedback-inhibition events illustrates how the combination of these ingredients alone may enforce allelic exclusion at the TCRbeta locus.
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http://dx.doi.org/10.4049/jimmunol.0904182DOI Listing
August 2010

Duality of enhancer functioning mode revealed in a reduced TCR beta gene enhancer knockin mouse model.

J Immunol 2009 Dec;183(12):7939-48

Centre d'Immunologie de Marseille-Luminy, Université Aix Marseille, Marseille, France.

The TCRbeta gene enhancer (Ebeta) commands TCRbeta gene expression through the lifespan of T lymphocytes. Genetic and molecular studies have implied that in early thymocytes, Ebeta directs chromatin opening over the Dbeta-Jbeta-Cbeta domains and triggers initial Dbeta-Jbeta recombination. In mature T cells, Ebeta is required for expression of the assembled TCRbeta gene. Whether these separate activities rely on distinct Ebeta regulatory sequences and involve differing modes of activation is unclear. Using gene targeting in mouse embryonic stem cells, we replaced Ebeta by a conserved core fragment (Ebeta169). We found that Ebeta169-carrying alleles were capable of sustaining beta gene expression and the development of mature T cells in homozygous knockin mice. Surprisingly, these procedures and underlying molecular transactions were affected to a wide range of degrees depending on the developmental stage. Early thymocytes barely achieved Dbeta-Jbeta germline transcription and recombination. In contrast, T cells displayed substantial though heterogeneous levels of VDJ-rearranged TCRbeta gene expression. Our results have implications regarding enhancer function in cells of the adaptive immune system and, potentially, TCRbeta gene recombination and allelic exclusion.
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http://dx.doi.org/10.4049/jimmunol.0902179DOI Listing
December 2009

Initiation of V(D)J recombination by Dbeta-associated recombination signal sequences: a critical control point in TCRbeta gene assembly.

PLoS One 2009 24;4(2):e4575. Epub 2009 Feb 24.

Centre d'Immunologie de Marseille-Luminy, Université Aix Marseille, Marseille, France.

T cell receptor (TCR) beta gene assembly by V(D)J recombination proceeds via successive Dbeta-to-Jbeta and Vbeta-to-DJbeta rearrangements. This two-step process is enforced by a constraint, termed beyond (B)12/23, which prohibits direct Vbeta-to-Jbeta rearrangements. However the B12/23 restriction does not explain the order of TCRbeta assembly for which the regulation remains an unresolved issue. The initiation of V(D)J recombination consists of the introduction of single-strand DNA nicks at recombination signal sequences (RSSs) containing a 12 base-pairs spacer. An RSS containing a 23 base-pairs spacer is then captured to form a 12/23 RSSs synapse leading to coupled DNA cleavage. Herein, we probed RSS nicks at the TCRbeta locus and found that nicks were only detectable at Dbeta-associated RSSs. This pattern implies that Dbeta 12RSS and, unexpectedly, Dbeta 23RSS initiate V(D)J recombination and capture their respective Vbeta or Jbeta RSS partner. Using both in vitro and in vivo assays, we further demonstrate that the Dbeta1 23RSS impedes cleavage at the adjacent Dbeta1 12RSS and consequently Vbeta-to-Dbeta1 rearrangement first requires the Dbeta1 23RSS excision. Altogether, our results provide the molecular explanation to the B12/23 constraint and also uncover a 'Dbeta1 23RSS-mediated' restriction operating beyond chromatin accessibility, which directs Dbeta1 ordered rearrangements.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0004575PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2642999PMC
April 2009

CoCAS: a ChIP-on-chip analysis suite.

Bioinformatics 2009 Apr 4;25(7):954-5. Epub 2009 Feb 4.

Centre d'Immunologie de Marseille-Luminy, CNRS, UMR6102, Inserm, U631, Université de la Méditerranée and Inserm, U928, TAGC, Marseille, France.

Motivation: High-density tiling microarrays are increasingly used in combination with ChIP assays to study transcriptional regulation. To ease the analysis of the large amounts of data generated by this approach, we have developed ChIP-on-chip Analysis Suite (CoCAS), a standalone software suite which implements optimized ChIP-on-chip data normalization, improved peak detection, as well as quality control reports. Our software allows dye swap, replicate correlation and connects easily with genome browsers and other peak detection algorithms. CoCAS can readily be used on the latest generation of Agilent high-density arrays. Also, the implemented peak detection methods are suitable for other datasets, including ChIP-Seq output.

Availability: The software is available for download along with a sample dataset at http://www.ciml.univ-mrs.fr/software/ferrier.htm.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btp075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2660873PMC
April 2009

Immunoreceptor tyrosine-based inhibition motifs: a quest in the past and future.

Immunol Rev 2008 Aug;224:11-43

Institut Pasteur, Département d'Immunologie, Unité d'Allergologie Moléculaire et Cellulaire, Paris, France.

Since an immunoreceptor tyrosine-based inhibition motif (ITIM) was first identified in the intracytoplasmic domain of Fc gammaRIIB, ITIMs have been found in a large number of inhibitory molecules that were shown to negatively regulate cell activation. Due to their wide tissue distribution and to the variety of their extracellular ligands, ITIM-containing molecules are involved in the control of a large spectrum of biological functions, mostly but not exclusively related to immunity. On the basis of sequence comparison, ITIMs were structurally defined as 6-amino acid sequences containing a tyrosine (Y) with loosely conserved N-terminal (Y-2) and C-terminal (Y+3) residues. Molecular analysis of signaling events demonstrated that when coaggregated with activating receptors, ITIMs are phosphorylated by Src-family tyrosine kinases, which enables them to recruit Src homology 2 domain-containing phosphatases that antagonize activation signals. Because ITIM-dependent negative regulation seems to be a fundamental regulatory mechanism, both in rodents and in humans, and because it can be used either as a target or as a powerful tool in various diseases, we undertook (i) a genome-wide search of potential novel ITIM-containing molecules in humans, mice, frogs, birds, and flies and (ii) a comparative analysis of potential ITIMs in major animal phyla, from mammals to protozoa. We found a surprisingly high number of potential ITIM-containing molecules, having a great diversity of extracellular domains, and being expressed by a variety of immune and non-immune cells. ITIMs could be traced back to the most primitive metazoa. The genes that encode ITIM-containing molecules that belong to the immunoglobulin superfamily or to the C-lectin family seem to derive from a common set of ancestor genes and to have dramatically expanded and diverged in Gnathostomata (from fish to mammals).
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http://dx.doi.org/10.1111/j.1600-065X.2008.00666.xDOI Listing
August 2008

Natural killer cells: from CD3(-)NKp46(+) to post-genomics meta-analyses.

Curr Opin Immunol 2007 Jun 17;19(3):365-72. Epub 2007 Apr 17.

Centre d'Immunologie de Marseille-Luminy, Université de la Mediterranée, Case 906, 13288 Marseille cedex 9, France.

The original definition of NK cells was based on their 'natural' cytolytic response against tumor cells and virus-infected cells in the absence of specific immunization. However, the term 'natural killer' reflects neither the education/maturation requirements before NK cells can kill nor the entirety of their biological functions. In light of new functional assays, genetic models and genomics analysis, we propose a more accurate definition of NK cells. This definition includes the phenotypical identification of NK cells as CD3(-)NKp46(+) cells across mammalian species. In general, this attempt to redefine NK cells also highlights the need to update the operational definition of cell types in the post-genomic area.
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http://dx.doi.org/10.1016/j.coi.2007.04.004DOI Listing
June 2007

Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46.

Proc Natl Acad Sci U S A 2007 Feb 20;104(9):3384-9. Epub 2007 Feb 20.

Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, 13288 Marseille, France.

Natural killer (NK) cells contribute to a variety of innate immune responses to viruses, tumors and allogeneic cells. However, our understanding of NK cell biology is severely limited by the lack of consensus phenotypic definition of these cells across species, by the lack of specific marker to visualize them in situ, and by the lack of a genetic model where NK cells may be selectively ablated. NKp46/CD335 is an Ig-like superfamily cell surface receptor involved in human NK cell activation. In addition to human, we show here that NKp46 is expressed by NK cells in all mouse strains analyzed, as well as in three common monkey species, prompting a unifying phenotypic definition of NK cells across species based on NKp46 cell surface expression. Mouse NKp46 triggers NK cell effector function and allows the detection of NK cells in situ. NKp46 expression parallels cell engagement into NK differentiation programs because it is detected on all NK cells from the immature CD122(+)NK1.1(+)DX5(-) stage and on a minute fraction of NK-like T cells, but not on CD1d-restricted NKT cells. Moreover, human NKp46 promoter drives NK cell selective expression both in vitro and in vivo. Using NKp46 promoter, we generated transgenic mice expressing EGFP and the diphtheria toxin (DT) receptor in NK cells. DT injection in these mice leads to a complete and selective NK cell ablation. This model paves a way for the in vivo characterization and preclinical assessment of NK cell biological function.
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http://dx.doi.org/10.1073/pnas.0609692104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1805551PMC
February 2007
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