La synapse immunologique : des modèles aux réalités

Bien des années après avoir découvert que, à l’instar des neurones, les cellules du système immunitaire communiquent entre elles au niveau de jonctions spécialisées de type synapse, la fonction de ces structures est ainsi toujours discutée. La raison de ce questionnement persistant est sans doute à rechercher dans une surinterprétation de l’organisation moléculaire particulière que l’on observe dans des conditions expérimentales peu physiologiques à la jonction cellule T/cellule présentatrice d’antigène, et dans une généralisation abusive du modèle qui en a été tiré. L’ambition de cet article est donc de faire le point sur les limites d’une vision provisoirement dominante de la synapse immunologique, et de présenter un autre point de vue sur cette structure et son fonctionnement.The notion of immunological synapse is generally associated to a concentric structure (a core of T cell receptors surrounded by a ring of adhesion molecules) often called “mature synapse”. This schematic view has been built on observations corresponding to peculiar experimental conditions: very high antigen concentration presented by surrogate APCs such as lipid bilayers or B lymphoma. These observations have been hastily constituted in a dogma that a “normal” synapse should look like this, should form only in the presence of antigen, and should trigger a “stop” signal that completely immobilizes the T cell. However, when analyzing the interaction between naive T cells and dendritic cells (DC), that are the only antigen-presenting cells able to activate naive T cells, a very different picture emerges. Firstly, T-DC synapses can form in the absence of antigen; therefore antigen recognition is not a prerequisite for synapse formation. Secondly, these antigen-independent synapses are likely to play several roles, including sensitization of T cells for later antigen detection, and delivery of survival signals. Thirdly, in vivo, naive T cells interacting with antigen-laden DC do not fully stop, but start to make transient contacts with DCs for a few minutes, before continuing their exploration. It is only after several hours of this process that T cells eventually immobilize. Fourthly, the structure of the T-DC synapse is clearly multifocal, the two cells interacting through several tens of tight appositions of a few tens of nm in diameter. These numerous tight appositions are reminiscent of the microclusters that have been recently described at the T-bilayer interface. Finally, synaptic signaling is not a transient initial event, but is sustained for hours. In particular, sustained activation of phosphatidylinositol 3-kinase allows the exclusion out of the nucleus of FoxO transcription factors, normally maintaining T cells in a quiescent state

A Novel ZAP-70 Dependent FRET Based Biosensor Reveals Kinase Activity at both the Immunological Synapse and the Antisynapse

Many hypotheses attempting to explain the speed and sensitivity with which a T-cell discriminates the antigens it encounters include a notion of relative spatial and temporal control of particular biochemical steps involved in the process. An essential step in T-cell receptor (TCR) mediated signalling is the activation of the protein tyrosine kinase ZAP-70. ZAP-70 is recruited to the TCR upon receptor engagement and, once activated, is responsible for the phosphorylation of the protein adaptor, Linker for Activation of T-cells, or LAT. LAT phosphorylation results in the recruitment of a signalosome including PLCγ1, Grb2/SOS, GADS and SLP-76. In order to examine the real time spatial and temporal evolution of ZAP-70 activity following TCR engagement in the immune synapse, we have developed ROZA, a novel FRET-based biosensor whose function is dependent upon ZAP-70 activity. This new probe not only provides a measurement of the kinetics of ZAP-70 activity, but also reveals the subcellular localization of the activity as well. Unexpectedly, ZAP-70 dependent FRET was observed not only at the T-cell -APC interface, but also at the opposite pole of the cell or “antisynapse”

Early T Cell Signalling Is Reversibly Altered in PD-1+ T Lymphocytes Infiltrating Human Tumors

To improve cancer immunotherapy, a better understanding of the weak efficiency of tumor-infiltrating T lymphocytes (TIL) is necessary. We have analyzed the functional state of human TIL immediately after resection of three types of tumors (NSCLC, melanoma and RCC). Several signalling pathways (calcium, phosphorylation of ERK and Akt) and cytokine secretion are affected to different extents in TIL, and show a partial spontaneous recovery within a few hours in culture. The global result is an anergy that is quite distinct from clonal anergy induced in vitro, and closer to adaptive tolerance in mice. PD-1 (programmed death -1) is systematically expressed by TIL and may contribute to their anergy by its mere expression, and not only when it interacts with its ligands PD-L1 or PD-L2, which are not expressed by every tumor. Indeed, the TCR-induced calcium and ERK responses were reduced in peripheral blood T cells transfected with PD-1. Inhibition by sodium stibogluconate of the SHP-1 and SHP-2 phosphatases that associate with several inhibitory receptors including PD-1, relieves part of the anergy apparent in TIL or in PD-1-transfected T cells. This work highlights some of the molecular modifications contributing to functional defects of human TIL

Long-term and large-scale multispecies dataset tracking population changes of common European breeding birds

Around fifteen thousand fieldworkers annually count breeding birds using standardized protocols in 28 European countries. The observations are collected by using country-specific and standardized protocols, validated, summarized and finally used for the production of continent-wide annual and long-term indices of population size changes of 170 species. Here, we present the database and provide a detailed summary of the methodology used for fieldwork and calculation of the relative population size change estimates. We also provide a brief overview of how the data are used in research, conservation and policy. We believe this unique database, based on decades of bird monitoring alongside the comprehensive summary of its methodology, will facilitate and encourage further use of the Pan-European Common Bird Monitoring Scheme results.publishedVersio

Mécanismes sous-jacents à la fatigue chronique, un symptôme trop souvent négligé

L’activation de l’hypothalamus par des signaux inflammatoires et/ou de stress peut déclencher celle de l’axe HPA (hypothalamic-pituitary-adrenal axis), qui intègre l’hypothalamus, l’hypophyse et la glande surrénale. L’activation aiguë de l’axe HPA est fondamentale pour la réponse fight or flight (« combats ou fuis »). Elle permet de mobiliser un maximum d’énergie pour un effort, tout en effaçant la fatigue. En revanche, son activation chronique diminue l’efficacité musculaire et entraîne une fatigue chronique. On discutera dans cette partie de plusieurs points stratégiques à considérer pour tenter de comprendre et de traiter ensemble inflammation et fatigue chroniques.</jats:p

Proposals of scientists

La loi sur la recherche de mars 2006 est un échec total sur trois points fondamentaux : la question des jeunes scientifiques, la confiance entre le monde scientifique et politique, et les moyens globaux. Des propositions précises existaient, mais le gouvernement a refusé d'en tenir compte

Mécanismes sous-jacents à la fatigue chronique, un symptôme trop souvent négligé: II. De l’immunité dérégulée à la neuroinflammation et ses conséquences

International audienceL’activation de l’hypothalamus par des signaux inflammatoires et/ou de stress peut déclencher celle de l’axe HPA (hypothalamic-pituitary-adrenal axis), qui intègre l’hypothalamus, l’hypophyse et la glande surrénale. L’activation aiguë de l’axe HPA est fondamentale pour la réponse fight or flight (« combats ou fuis »). Elle permet de mobiliser un maximum d’énergie pour un effort, tout en effaçant la fatigue. En revanche, son activation chronique diminue l’efficacité musculaire et entraîne une fatigue chronique. On discutera dans cette partie de plusieurs points stratégiques à considérer pour tenter de comprendre et de traiter ensemble inflammation et fatigue chroniques

A New Light on T Cell Activation Shed by a Photoactivatable Agonist

Which molecular events control the initiation of a T cell response? In this issue of Immunity, Huse et al. (2007) describe a photoactivatable agonist that will substantially improve our ability to investigate this phenomenon