Université PSL



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Innate Immune Signals Induce Anterograde Endosome Transport Promoting MHC Class I Cross-Presentation.
Weimershaus M, Mauvais FX, Saveanu L, Adiko C, Babdor J, Abramova A, Montealegre S, Lawand M, Evnouchidou I, Huber KJ, Chadt A, Zwick M, Vargas P, Dussiot M, Lennon-Dumenil AM, Brocker T, Al-Hasani H, van Endert P.
Cell Reports - 24(13) 3568-3581 - doi: 10.1016/j.celrep.2018.08.041 - 2018
Both cross-presentation of antigens by dendritic cells, a key pathway triggering T cell immunity and immune tolerance, and survival of several pathogens residing in intracellular vacuoles are intimately linked to delayed maturation of vesicles containing internalized antigens and microbes. However, how early endosome or phagosome identity is maintained is incompletely understood. We show that Toll-like receptor 4 (TLR4) and Fc receptor ligation induces interaction of the GTPase Rab14 with the kinesin KIF16b mediating plus-end-directed microtubule transport of endosomes. As a result, Rab14 recruitment to phagosomes delays their maturation and killing of an internalized pathogen. Enhancing anterograde transport by overexpressing Rab14, promoting the GTP-bound Rab14 state, or inhibiting retrograde transport upregulates cross-presentation. Conversely, reducing Rab14 expression, destabilizing Rab14 endosomes, and inhibiting anterograde microtubule transport by Kif16b knockdown compromise cross-presentation. Therefore, regulation of early endosome trafficking by innate immune signals is a critical parameter in cross-presentation by dendritic cells.
Diversification of human plasmacytoid predendritic cells in response to a single stimulus
Alculumbre SG, Saint-André V1, Di Domizio J, Vargas P, Sirven P, Bost P, Maurin M, Maiuri P, Wery M, Roman MS, Savey L, Touzot M, Terrier B, Saadoun D, Conrad C, Gilliet M, Morillon A, Soumelis V.
Nat Immunol. - 19(1) 63-75 - doi: 10.1038/s41590-017-0012-z - 2018
Innate immune cells adjust to microbial and inflammatory stimuli through a process termed environmental plasticity, which links a given individual stimulus to a unique activated state. Here, we report that activation of human plasmacytoid predendritic cells (pDCs) with a single microbial or cytokine stimulus triggers cell diversification into three stable subpopulations (P1-P3). P1-pDCs (PD-L1+CD80-) displayed a plasmacytoid morphology and specialization for type I interferon production. P3-pDCs (PD-L1-CD80+) adopted a dendritic morphology and adaptive immune functions. P2-pDCs (PD-L1+CD80+) displayed both innate and adaptive functions. Each subpopulation expressed a specific coding- and long-noncoding-RNA signature and was stable after secondary stimulation. P1-pDCs were detected in samples from patients with lupus or psoriasis. pDC diversification was independent of cell divisions or preexisting heterogeneity within steady-state pDCs but was controlled by a TNF autocrine and/or paracrine communication loop. Our findings reveal a novel mechanism for diversity and division of labor in innate immune cells.
Spontaneous migration of cellular aggregates from giant keratocytes to running spheroids
Grégory Beaune, Carles Blanch-Mercader, Stéphane Douezan, Julien Dumond, David Gonzalez-Rodriguez, Damien Cuvelier, Thierry Ondarçuhu, Pierre Sens, Sylvie Dufour, Michael P. Murrell, and Françoise Brochard-Wyart
Cell Sci - 115 (51) 12926-12931 - doi.org/10.1073/pnas.1811348115 - 2018
Despite extensive knowledge on the mechanisms that drive single-cell migration, those governing the migration of cell clusters, as occurring during embryonic development and cancer metastasis, remain poorly understood. Here, we investigate the collective migration of cell on adhesive gels with variable rigidity, using 3D cellular aggregates as a model system. After initial adhesion to the substrate, aggregates spread by expanding outward a cell monolayer, whose dynamics is optimal in a narrow range of rigidities. Fast expansion gives rise to the accumulation of mechanical tension that leads to the rupture of cell–cell contacts and the nucleation of holes within the monolayer, which becomes unstable and undergoes dewetting like a liquid film. This leads to a symmetry breaking and causes the entire aggregate to move as a single entity. Varying the substrate rigidity modulates the extent of dewetting and induces different modes of aggregate motion: “giant keratocytes,” where the lamellipodium is a cell monolayer that expands at the front and retracts at the back; “penguins,” characterized by bipedal locomotion; and “running spheroids,” for nonspreading aggregates. We characterize these diverse modes of collective migration by quantifying the flows and forces that drive them, and we unveil the fundamental physical principles that govern these behaviors, which underscore the biological predisposition of living material to migrate, independent of length scale.
Adhesion to nanofibers drives cell membrane remodeling through one-dimensional wetting.
Arthur Charles-Orszag, Feng-Ching Tsai, Daria Bonazzi, Valeria Manriquez, Martin Sachse, Adeline Mallet, Audrey Salles, Keira Melican, Ralitza Staneva, Aurélie Bertin, Corinne Millien, Sylvie Goussard, Pierre Lafaye, Spencer Shorte, Matthieu Piel, Jacomi
Nature Communications - 4450 : - Adhesion to nanofibers drives cell membrane remodeling through one-dimensional wetting. - 2018
The shape of cellular membranes is highly regulated by a set of conserved mechanisms that can be manipulated by bacterial pathogens to infect cells. Remodeling of the plasma membrane of endothelial cells by the bacterium Neisseria meningitidis is thought to be essential during the blood phase of meningococcal infection, but the underlying mechanisms are unclear. Here we show that plasma membrane remodeling occurs independently of F-actin, along meningococcal type IV pili fibers, by a physical mechanism that we term ‘one-dimensional’ membrane wetting. We provide a theoretical model that describes the physical basis of one-dimensional wetting and show that this mechanism occurs in model membranes interacting with nanofibers, and in human cells interacting with extracellular matrix meshworks. We propose one-dimensional wetting as a new general principle driving the interaction of cells with their environment at the nanoscale that is diverted by meningococci during infection.
Size control in mammalian cells involves modulation of both growth rate and cell cycle duration.
Article | OPEN | Published: 16 August 2018 Size control in mammalian cells involves modulation of both growth rate and cell cycle duration Clotilde Cadart, Sylvain Monnier, Jacopo Grilli, Pablo J. Sáez, Nishit Srivastava, Rafaele Attia, Emmanuel Terriac
Nature Communications - 9 3275 - DOI : 10.1038/s41467-018-05393-0 - 2018
Despite decades of research, how mammalian cell size is controlled remains unclear because of the difficulty of directly measuring growth at the single-cell level. Here we report direct measurements of single-cell volumes over entire cell cycles on various mammalian cell lines and primary human cells. We find that, in a majority of cell types, the volume added across the cell cycle shows little or no correlation to cell birth size, a homeostatic behavior called “adder”. This behavior involves modulation of G1 or S-G2 duration and modulation of growth rate. The precise combination of these mechanisms depends on the cell type and the growth condition. We have developed a mathematical framework to compare size homeostasis in datasets ranging from bacteria to mammalian cells. This reveals that a near-adder behavior is the most common type of size control and highlights the importance of growth rate modulation to size control in mammalian cells.
LINC complex-Lis1 interplay controls MT1-MMP matrix digest-on-demand response for confined tumor cell migration.
Elvira Infante, Alessia Castagnino, Robin Ferrari, Pedro Monteiro, Sonia Agüera-González, Perrine Paul-Gilloteaux, Mélanie J Domingues, Paolo Maiuri, Matthew Raab, Catherine M Shanahan, Alexandre Baffet, Matthieu Piel, Edgar R Gomes, Philippe Chavrier
Nature Communications - 9 2443 - DOI : 10.1038/s41467-018-04865-7 - 2018
Cancer cells’ ability to migrate through constricting pores in the tissue matrix is limited by nuclear stiffness. MT1-MMP contributes to metastasis by widening matrix pores, facilitating confined migration. Here, we show that modulation of matrix pore size or of lamin A expression known to modulate nuclear stiffness directly impinges on levels of MT1-MMP-mediated pericellular collagenolysis by cancer cells. A component of this adaptive response is the centrosome-centered distribution of MT1-MMP intracellular storage compartments ahead of the nucleus. We further show that this response, including invadopodia formation in association with confining matrix fibrils, requires an intact connection between the nucleus and the centrosome via the linker of nucleoskeleton and cytoskeleton (LINC) complex protein nesprin-2 and dynein adaptor Lis1. Our results uncover a digest-on-demand strategy for nuclear translocation through constricted spaces whereby confined migration triggers polarization of MT1-MMP storage compartments and matrix proteolysis in front of the nucleus depending on nucleus-microtubule linkage.
Role of calcium permeable channels in dendritic cell migration.
Sáez PJ, Sáez JC, Lennon-Duménil AM, Vargas P.
Curr Opin Immunol. - 52 74-80 - doi: 10.1016/j.coi.2018.04 - 2018
Calcium ion (Ca2+) is an essential second messenger involved in multiple cellular and subcellular processes. Ca2+ can be released and sensed globally or locally within cells, providing complex signals of variable amplitudes and time-scales. The key function of Ca2+ in the regulation of acto-myosin contractility has provided a simple explanation for its role in the regulation of immune cell migration. However, many questions remain, including the identity of the Ca2+ stores, channels and upstream signals involved in this process. Here, we focus on dendritic cells (DCs), because their immune sentinel function heavily relies on their capacity to migrate within tissues and later on between tissues and lymphoid organs. Deciphering the mechanisms by which cytoplasmic Ca2+ regulate DC migration should shed light on their role in initiating and tuning immune responses.
Mixed Copolymer Adlayers Allowing Reversible Thermal Control of Single Cell Aspect Ratio.
Dalier F, Dubacheva GV, Coniel M, Zanchi D, Galtayries A, Piel M, Marie E, Tribet C.
ACS Appl Mater Interfaces - 10(3) 2253-2258 - doi: 10.1021/acsami.7b18513. - 2018
Dynamic guidance of living cells is achieved by fine-tuning and spatiotemporal modulation on artificial polymer layers enabling reversible peptide display. Adjustment of surface composition and interactions is obtained by coadsorption of mixed poly(lysine) derivatives, grafted with either repellent PEG, RGD adhesion peptides, or T-responsive poly(N-isopropylacrylamide) strands. Deposition of mixed adlayers provides a straightforward mean to optimize complex substrates, which is here implemented to achieve (1) thermal control of ligand accessibility and (2) adjustment of relative adhesiveness between adjacent micropatterns, while preserving cell attachment during thermal cycles. The reversible polarization of HeLa cells along orthogonal stripes mimics guidance along natural matrices.
Retraction Notice to: FMN2 Makes Perinuclear Actin to Protect Nuclei during Confined Migration and Promote Metastasis.
Skau CT, Fischer RS, Gurel P, Thiam HR, Tubbs A, Baird MA, Davidson MW, Piel M, Alushin GM, Nussenzweig A, Steeg PS, Waterman CM.
Cell - 173(2) 529 - doi: 10.1016/j.cell.2018.03.058 - 2018
FMN2 Makes Perinuclear Actin to Protect Nuclei during Confined Migration and Promote Metastasis. [Cell. 2016]
Leukocyte Migration and Deformation in Collagen Gels and Microfabricated Constrictions
Sáez PJ, Barbier L, Attia R, Thiam HR, Piel M, Vargas P.
Methods Mol Biol. - 1749 361-373 - doi: 10.1007/978-1-4939-7701-7_26. - 2018
In multicellular organisms, cell migration is a complex process. Examples of this are observed during cell motility in the interstitial space, full of extracellular matrix fibers, or when cells pass through endothelial layers to colonize or exit specific tissues. A common parameter for both situations is the fast adaptation of the cellular shape to their irregular landscape. In this chapter, we describe two methods to study cell migration in complex environments. The first one consists in a multichamber device for the visualization of cell haptotaxis toward the collagen-binding chemokine CCL21. This method is used to study cell migration as well as deformations during directed motility, as in the interstitial space. The second one consists in microfabricated channels connected to small constrictions. This procedure allows the study of cell deformations when single cells migrate through small holes and it is analogous to passage of cells through endothelial layers, resulting in a simplified system to study the mechanisms operating during transvasation. Both methods combined provide a powerful hub for the study of cell plasticity during migration in complex environments.

346 publications.