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Team Publications Spatio-temporal Regulation of Antigen Presentation Year of publication 2009 Fernando E Sepulveda, Sophia Maschalidi, Renaud Colisson, Lea Heslop, Cristina Ghirelli, Emna Sakka, Ana-Maria Lennon-Duménil, Sebastian Amigorena, Lucien Cabanie, Bénédicte Manoury (2009 Nov 3) Critical role for asparagine endopeptidase in endocytic Toll-like receptor signaling in dendritic cells. Immunity : 737-48 : DOI : 10.1016/j.immuni.2009.09.013 Summary Intracellular Toll-like receptor 3 (TLR3), TLR7, and TLR9 localize in endosomes and recognize single-stranded RNA and nucleotides from viruses and bacteria. This interaction induces their conformational changes resulting in the production of proinflammatory cytokines and upregulation of cell surface molecules. TLR9 requires a proteolytic cleavage for its signaling. Here, we report that myeloid and plasmacytoid dendritic cells (DCs) deficient for the asparagine endopeptidase (AEP), a cysteine lysosomal protease, showed a decrease in the secretion of proinflammatory cytokines in response to TLR9 stimulation in vitro and in vivo. Upon stimulation, full-length TLR9 was cleaved into a 72 kDa fragment and this processing was strongly reduced in DCs lacking AEP. Processed TLR9 coeluted with the adaptor molecule MyD88 and AEP after size exclusion chromatography. When expressed in AEPdeficient DCs, the 72 kDa proteolytic fragment restored TLR9 signaling. Thus, our results identify an endocytic protease playing a critical role in TLR processing and signaling in DCs. Laurence Bougnères, Julie Helft, Sangeeta Tiwari, Pablo Vargas, Benny Hung-Junn Chang, Lawrence Chan, Laura Campisi, Gregoire Lauvau, Stephanie Hugues, Pradeep Kumar, Alice O Kamphorst, Ana-Maria Lennon Dumenil, Michel Nussenzweig, John D MacMicking, Sebastian Amigorena, Pierre Guermonprez (2009 Aug 25) A role for lipid bodies in the cross-presentation of phagocytosed antigens by MHC class I in dendritic cells. Immunity : 232-44 : DOI : 10.1016/j.immuni.2009.06.022 Summary Dendritic cells (DCs) have the striking ability to cross-present exogenous antigens in association with major histocompatibility complex (MHC) class I to CD8(+) T cells. However, the intracellular pathways underlying cross-presentation remain ill defined. Current models involve cytosolic proteolysis of antigens by the proteasome and peptide import into endoplasmic reticulum (ER) or phagosomal lumen by the transporters associated with antigen processing (TAP1 and TAP2). Here, we show that DCs expressed an ER-resident 47 kDa immune-related GTPase, Igtp (Irgm3). Igtp resides on ER and lipid body (LB) membranes where it binds the LB coat component ADFP. Inactivation of genes encoding for either Igtp or ADFP led to defects in LB formation in DCs and severely impaired cross-presentation of phagocytosed antigens to CD8(+) T cells but not antigen presentation to CD4(+) T cells. We INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 1 Team Publications Spatio-temporal Regulation of Antigen Presentation thus define a new role for LB organelles in regulating cross-presentation of exogenous antigens to CD8(+) T lymphocytes in DCs. Maria-Isabel Yuseff, Danielle Lankar, Ana-Maria Lennon-Duménil (2009 May 7) Dynamics of membrane trafficking downstream of B and T cell receptor engagement: impact on immune synapses. Traffic (Copenhagen, Denmark) : 629-36 : DOI : 10.1111/j.1600-0854.2009.00913.x Summary The onset of an adaptive immune response requires the activation of T and B lymphocytes by antigen-presenting cells, through a specialized form of intercellular communication, known as the immunological synapse (IS). In B lymphocytes the IS promotes efficient recognition and acquisition of membrane-bound Ags, while in T cells, it modulates the T cell response upon exposure to peptide-major histocompatibility complexes. In this review, we highlight the similarities that determine B and T cell activation, focusing on immune receptor downstream signaling events that lead to synapse formation. We stress the notion that polarization of T and B lymphocytes characterized by global changes in cytoskeleton and membrane trafficking modulates synapse structure and function, thus determining lymphocyte effector functions and fate. Benoît Carpentier, Paolo Pierobon, Claire Hivroz, Nelly Henry (2009 Mar 11) T-cell artificial focal triggering tools: linking surface interactions with cell response. PloS one : e4784 : DOI : 10.1371/journal.pone.0004784 Summary T-cell activation is a key event in the immune system, involving the interaction of several receptor ligand pairs in a complex intercellular contact that forms between T-cell and antigen-presenting cells. Molecular components implicated in contact formation have been identified, but the mechanism of activation and the link between molecular interactions and cell response remain poorly understood due to the complexity and dynamics exhibited by whole cell-cell conjugates. Here we demonstrate that simplified model colloids grafted so as to target appropriate cell receptors can be efficiently used to explore the relationship of receptor engagement to the T-cell response. Using immortalized Jurkat T cells, we monitored both binding and activation events, as seen by changes in the intracellular calcium concentration. Our experimental strategy used flow cytometry analysis to follow the short time scale cell response in populations of thousands of cells. We targeted both T-cell receptor CD3 (TCR/CD3) and leukocyte-function-associated antigen (LFA-1) alone or in combination. We showed that specific engagement of TCR/CD3 with a single particle induced a transient calcium signal, confirming previous results and validating our approach. By decreasing anti-CD3 particle density, we showed that contact nucleation was the most crucial and determining step in the cell-particle interaction under dynamic conditions, due to INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 2 Team Publications Spatio-temporal Regulation of Antigen Presentation shear stress produced by hydrodynamic flow. Introduction of LFA-1 adhesion molecule ligands at the surface of the particle overcame this limitation and elucidated the low TCR/CD3 ligand density regime. Despite their simplicity, model colloids induced relevant biological responses which consistently echoed whole cell behavior. We thus concluded that this biophysical approach provides useful tools for investigating initial events in T-cell activation, and should enable the design of intelligent artificial systems for adoptive immunotherapy. INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 3