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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.
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