Réponses immunitaires et cancer

Publications de l’équipe

Année de publication : 2005

Jean-Sébastien Silvestre, Clotilde Théry, Ghislaine Hamard, Jacques Boddaert, Barbara Aguilar, Alain Delcayre, Christophe Houbron, Radia Tamarat, Olivier Blanc-Brude, Sylvia Heeneman, Michel Clergue, Micheline Duriez, Régine Merval, Bernard Lévy, Alain Tedgui, Sebastian Amigorena, Ziad Mallat (2005 Apr 19)

Lactadherin promotes VEGF-dependent neovascularization.

Nature medicine : 499-506 En savoir plus
Résumé

Vascular endothelial growth factor (VEGF)-induced blood vessel growth is involved in both physiological and pathological angiogenesis and requires integrin-mediated signaling. We now show that an integrin-binding protein initially described in milk-fat globule, MFG-E8 (also known as lactadherin), is expressed in and around blood vessels and has a crucial role in VEGF-dependent neovascularization in the adult mouse. Using neutralizing antibodies and lactadherin-deficient animals, we show that lactadherin interacts with alphavbeta3 and alphavbeta5 integrins and alters both VEGF-dependent Akt phosphorylation and neovascularization. In the absence of VEGF, lactadherin administration induced alphavbeta3- and alphavbeta5-dependent Akt phosphorylation in endothelial cells in vitro and strongly improved postischemic neovascularization in vivo. These results show a crucial role for lactadherin in VEGF-dependent neovascularization and identify lactadherin as an important target for the modulation of neovascularization.

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Elodie Segura, Carole Nicco, Bérangère Lombard, Philippe Véron, Graça Raposo, Frédéric Batteux, Sebastian Amigorena, Clotilde Théry (2005 Mar 26)

ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming.

Blood : 216-23 En savoir plus
Résumé

Exosomes are secreted vesicles formed in late endocytic compartments. Immature dendritic cells (DCs) secrete exosomes, which transfer functional major histocompatibility complex (MHC)-peptide complexes to other DCs. Since immature and mature DCs induce different functional T-cell responses (ie, tolerance versus priming), we asked whether DC maturation also influenced the priming abilities of their exosomes. We show that exosomes secreted by lipopolysaccharide (LPS)-treated mature DCs are 50- to 100-fold more potent to induce antigen-specific T-cell activation in vitro than exosomes from immature DCs. In vitro, exosomes from mature DCs transfer to B lymphocytes the ability to prime naive T cells. In vivo, only mature exosomes trigger effector T-cell responses, leading to fast skin graft rejection. Proteomic and biochemical analyses revealed that mature exosomes are enriched in MHC class II, B7.2, intercellular adhesion molecule 1 (ICAM-1), and bear little milk-fat globule-epidermal growth factor-factor VIII (MFG-E8) as compared with immature exosomes. Functional analysis using DC-derived exosomes from knock-out mice showed that MHC class II and ICAM-1 are required for mature exosomes to prime naive T cells, whereas B7.2 and MFG-E8 are dispensable. Therefore, changes in protein composition and priming abilities of exosomes reflect the maturation signals received by DCs.

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Année de publication : 2004

Pierre Guermonprez, Sebastian Amigorena (2004 Dec 14)

Pathways for antigen cross presentation.

Springer seminars in immunopathology : 257-71 En savoir plus
Résumé

Dendritic cells (DCs) have the unique ability to capture cellular tissue antigens, and to present them on MHC class I molecules to antigen-specific CD8(+) T lymphocytes after migration to the draining lymph nodes. This process, called « cross presentation » can lead either to the tolerization or activation of antigen-specific CD8(+) T cells. Antigen capture is believed to occur by phagocytosis of antigen-bearing dead cells. Recent studies suggest that the antigen transferred from the phagocytosed cell to the DC during cross presentation is a proteasome substrate, rather than a proteasomal degradation product. In most cases, the formation of the peptide-MHC class I complexes in DCs requires the export of protein antigens from phagosomes to the cytosol, where they undergo proteasomal degradation. The resulting peptides are then translocated by TAP to the lumen of a cross presentation-loading compartment, for association to MHC class I under the control of chaperones and oxido-reductases. This loading compartment may be either the endoplasmic reticulum (ER) or a mix phagosome-ER compartment. MHC class I egress from the loading compartment to cell surface remains to be analyzed.

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Stéphanie Hugues, Luc Fetler, Laura Bonifaz, Julie Helft, François Amblard, Sebastian Amigorena (2004 Nov 2)

Distinct T cell dynamics in lymph nodes during the induction of tolerance and immunity.

Nature immunology : 1235-42 En savoir plus
Résumé

Induction of immunity and peripheral tolerance requires contacts between antigen-bearing dendritic cells (DCs) and cognate T cells. Using real-time two-photon microscopy, we have analyzed the dynamics of CD8(+) T cells in lymph nodes during the induction of antigen-specific immunity or tolerance. At 15-20 h after the induction of immunity, T cells stopped moving and established prolonged interactions with DCs. In tolerogenic conditions, despite effective initial T cell activation and proliferation, naive T cells remained motile and established serial brief contacts with multiple DCs. Thus, stable DC-T cell interactions occur during the induction of priming, whereas brief contacts may contribute to the induction of T cell tolerance.

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Pierre Guermonprez, Sebastian Amigorena (2004 Sep 17)

[An export-reimport model for cross presentation of particulate antigens by MHC class I molecules in dentritic cells].

Journal de la Société de biologie : 121-2 En savoir plus
Résumé

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Federica Benvenuti, Stephanie Hugues, Marita Walmsley, Sandra Ruf, Luc Fetler, Michel Popoff, Victor L J Tybulewicz, Sebastian Amigorena (2004 Aug 25)

Requirement of Rac1 and Rac2 expression by mature dendritic cells for T cell priming.

Science (New York, N.Y.) : 1150-3 En savoir plus
Résumé

Upon maturation, dendritic cells (DCs) acquire the unique ability to activate naïve T cells. We used time-lapse video microscopy and two-photon imaging of intact lymph nodes to show that after establishing initial contact between their dendrites and naïve T lymphocytes, mature DCs migrate toward the contacted lymphocytes. Subsequently, the DCs tightly entrap the T cells within a complex net of membrane extensions. The Rho family guanosine triphosphatases Rac1 and Rac2 but not Rho itself control the formation of dendrites in mature DCs, their polarized short-range migration toward T cells, and T cell priming.

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Nicolas Blanchard, Maud Decraene, Kun Yang, Francesc Miro-Mur, Sebastian Amigorena, Claire Hivroz (2004 Aug 24)

Strong and durable TCR clustering at the T/dendritic cell immune synapse is not required for NFAT activation and IFN-gamma production in human CD4+ T cells.

Journal of immunology (Baltimore, Md. : 1950) : 3062-72 En savoir plus
Résumé

The exact function of TCR clustering and organized macromolecular patterns at the immune synapse between APCs and T lymphocytes is unclear. Using human immature or mature dendritic cells (DCs) and autologous CD4(+) effector T cells, we demonstrate that, within a given conjugate, mature DCs induce strong and long-lasting TCR clustering and protein kinase C-theta translocation in a superantigen dose-dependent manner. Moreover, mature DCs promote CD43 exclusion in a dose-independent manner. In contrast, immature DCs are less potent at inducing these molecular rearrangements. Using these models to correlate T cell functions with the frequency, the intensity, and the duration of TCR clustering, we show, in Jurkat T cells, that weak and transient TCR clustering is sufficient to promote TCR down-modulation, protein kinase C-theta translocation at the synapse, and substantial NFAT transcriptional activation. Moreover, we show, in CD4(+) T cell blasts, that strong TCR clustering is required for neither TCR down-modulation nor optimal IFN-gamma production. Together, our results demonstrate that some CD4(+) functional responses, such as cytokine production, are independent of central supramolecular activation cluster formation.

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Beatriz C Gil-Torregrosa, Ana Maria Lennon-Duménil, Benedikt Kessler, Pierre Guermonprez, Hidde L Ploegh, Doriana Fruci, Peter van Endert, Sebastian Amigorena (2004 Feb 10)

Control of cross-presentation during dendritic cell maturation.

European journal of immunology : 398-407 En savoir plus
Résumé

The initiation of most cytotoxic immune responses requires MHC class I-restricted presentation of internalized antigens to CD8(+) T lymphocytes, a process called cross-presentation. In dendritic cells (DC), the only antigen-presenting cells that activate naive T cells, cross-presentation is particularly efficient after internalization of opsonized antigens or immune complexes, which are cross-presented through a proteasome- and transporter associated with antigen processing (TAP)-dependent MHC class I antigen presentation pathway. We now show that FcgammaR-mediated cross-presentation is tightly regulated during DC maturation. Cross-presentation increases soon after activation by lipopolysaccharides, and it is then inhibited in fully mature cells. The initial induction of cross-presentation results from an increase of both antigen internalization and delivery to the cytosol, and from a slight rise in the activity of the proteasome and TAP. The subsequent block of cross-presentation in mature DC is a consequence of the selective down-modulation of antigen internalization and cytosolic delivery, while proteasome and TAP activities continue to rise. Therefore, FcgammaR-mediated cross-presentation is regulated during DC maturation by the selective control of antigen internalization and transport to the cytosol.

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Année de publication : 2003

Federica Benvenuti, Cecile Lagaudrière-Gesbert, Isabelle Grandjean, Carolina Jancic, Claire Hivroz, Alain Trautmann, Olivier Lantz, Sebastian Amigorena (2003 Dec 23)

Dendritic cell maturation controls adhesion, synapse formation, and the duration of the interactions with naive T lymphocytes.

Journal of immunology (Baltimore, Md. : 1950) : 292-301 En savoir plus
Résumé

The initiation of adaptive immune responses requires the direct interaction of dendritic cells (DCs) with naive T lymphocytes. It is well established that the maturation state of DCs has a critical impact on the outcome of the response. We show here that mature DCs form stable conjugates with naive T cells and induce the formation of organized immune synapses. Immature DCs, in contrast, form few stable conjugates with no organized immune synapses. A dynamic analysis revealed that mature DCs can form long-lasting interactions with naive T cells, even in the absence of Ag. Immature DCs, in contrast, established only short intermittent contacts, suggesting that the premature termination of the interaction prevents the formation of organized immune synapses and full T cell activation.

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Pierre Guermonprez, Loredana Saveanu, Monique Kleijmeer, Jean Davoust, Peter Van Endert, Sebastian Amigorena (2003 Sep 26)

ER-phagosome fusion defines an MHC class I cross-presentation compartment in dendritic cells.

Nature : 397-402 En savoir plus
Résumé

Induction of cytotoxic T-cell immunity requires the phagocytosis of pathogens, virus-infected or dead tumour cells by dendritic cells. Peptides derived from phagocytosed antigens are then presented to CD8+ T lymphocytes on major histocompatibility complex (MHC) class I molecules, a process called « cross-presentation ». After phagocytosis, antigens are exported into the cytosol and degraded by the proteasome. The resulting peptides are thought to be translocated into the lumen of the endoplasmic reticulum (ER) by specific transporters associated with antigen presentation (TAP), and loaded onto MHC class I molecules by a complex « loading machinery » (which includes tapasin, calreticulin and Erp57). Here we show that soon after or during formation, phagosomes fuse with the ER. After antigen export to the cytosol and degradation by the proteasome, peptides are translocated by TAP into the lumen of the same phagosomes, before loading on phagosomal MHC class I molecules. Therefore, cross-presentation in dendritic cells occurs in a specialized, self-sufficient, ER-phagosome mix compartment.

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Christine Sedlik, Daniel Orbach, Philippe Veron, Edina Schweighoffer, Francesco Colucci, Romina Gamberale, Andrea Ioan-Facsinay, Sjef Verbeek, Paola Ricciardi-Castagnoli, Christian Bonnerot, Victor L J Tybulewicz, James Di Santo, Sebastian Amigorena (2003 Jan 9)

A critical role for Syk protein tyrosine kinase in Fc receptor-mediated antigen presentation and induction of dendritic cell maturation.

Journal of immunology (Baltimore, Md. : 1950) : 846-52 En savoir plus
Résumé

Dendritic cells (DCs) are the only APCs capable of initiating adaptive immune responses. The initiation of immune responses requires that DCs 1) internalize and present Ags; and 2) undergo a differentiation process, called « maturation », which transforms DCs into efficient APCs. DC maturation may be initiated by the engagement of different surface receptors, including certain cytokine receptors (such as TNFR), Toll-like receptors, CD40, and FcRs. The early activation events that link receptor engagement and DC maturation are not well characterized. We found that FcR engagement by immune complexes induced the phosphorylation of Syk, a protein tyrosine kinase acting immediately downstream of FcRs. Syk was dispensable for DC differentiation in vitro and in vivo, but was strictly required for immune complexes internalization and subsequent Ag presentation to T lymphocytes. Importantly, Syk was also required for the induction of DC maturation and IL-12 production after FcR engagement, but not after engagement of other surface receptors, such as TNFR or Toll-like receptors. Therefore, protein tyrosine phosphorylation by Syk represents a novel pathway for the induction of DC maturation.

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Année de publication : 2002

Clotilde Théry, Livine Duban, Elodie Segura, Philippe Véron, Olivier Lantz, Sebastian Amigorena (2002 Nov 12)

Indirect activation of naïve CD4+ T cells by dendritic cell-derived exosomes.

Nature immunology : 1156-62 En savoir plus
Résumé

Dendritic cells (DCs) secrete vesicles of endosomal origin, called exosomes, that bear major histocompatibility complex (MHC) and T cell costimulatory molecules. Here, we found that injection of antigen- or peptide-bearing exosomes induced antigen-specific naïve CD4+ T cell activation in vivo. In vitro, exosomes did not induce antigen-dependent T cell stimulation unless mature CD8alpha- DCs were also present in the cultures. These mature DCs could be MHC class II-negative, but had to bear CD80 and CD86. Therefore, in addition to carrying antigen, exosomes promote the exchange of functional peptide-MHC complexes between DCs. Such a mechanism may increase the number of DCs bearing a particular peptide, thus amplifying the initiation of primary adaptive immune responses.

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Clotilde Théry, Laurence Zitvogel, Sebastian Amigorena (2002 Aug 3)

Exosomes: composition, biogenesis and function.

Nature reviews. Immunology : 569-79 En savoir plus
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Pierre Guermonprez, Jenny Valladeau, Laurence Zitvogel, Clotilde Théry, Sebastian Amigorena (2002 Feb 28)

Antigen presentation and T cell stimulation by dendritic cells.

Annual review of immunology : 621-67 En savoir plus
Résumé

Dendritic cells take up antigens in peripheral tissues, process them into proteolytic peptides, and load these peptides onto major histocompatibility complex (MHC) class I and II molecules. Dendritic cells then migrate to secondary lymphoid organs and become competent to present antigens to T lymphocytes, thus initiating antigen-specific immune responses, or immunological tolerance. Antigen presentation in dendritic cells is finely regulated: antigen uptake, intracellular transport and degradation, and the traffic of MHC molecules are different in dendritic cells as compared to other antigen-presenting cells. These specializations account for dendritic cells’ unique role in the initiation of immune responses and the induction of tolerance.

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Sebastian Amigorena (2002 Jan 10)

Fc gamma receptors and cross-presentation in dendritic cells.

The Journal of experimental medicine : F1-3 En savoir plus
Résumé

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