Lymphocyte Cell Biology - CNRS URA 1961  


  HEADDr Andrés ALCOVER / andres.alcover@pasteur.fr
  MEMBERSChercheurs statutaires : Dr Vincenzo Di BARTOLO / Dr Maria-Isabel THOULOUZE.
Chercheurs post-doctoraux : Dr Rémi LASSERRE / Dr Helena MARTINS-SOARES
Etudiants en thèse : Ana-Monica PAIS-CORREIA / Valentina ROBBIATI
Technicienne : Céline CUCHE
Secrétaire : Cécile ROUX


  Annual Report

Following antigen recognition, T cells polarize towards antigen presenting cells concentrating T cell receptors, adhesion molecules, signaling effectors and cytoskeleton components at the antigen presenting cell contact site. This cellular contact was named the immunological synapse, since it ensures the communication between the T cell and the antigen-presenting cell.

We investigate the molecular mechanisms that generate immunological synapses and their role in T cell activation. We also study how lymphotropic retroviruses hijack the mechanisms that generate immunological synapses to modulate T cell responses and to spread more efficiently from cell to cell.

Tuning T cell activation at the immunological synapse.

We previously showed that ezrin, a protein that links the membrane with the actin cytoskeleton, is involved in the formation of the immunological synapse and in T cell activation (Roumier et al., Immunity, 2001). By specifically depleting ezrin from T cells, using siRNA, we recently unraveled that Ezrin plays a key role in the crosstalk between the cortical actin cytoskeleton, the signal transduction machinery and the microtubule networks, setting the fine architecture of the immunological synapse and tuning T cell receptor signaling. Moreover, we have recently described a novel interaction between the scaffold protein SLP-76 and members of the 14-3-3 protein family (Di Bartolo et al., JEM, 2007) and we have demonstrated that this interaction is important for the negative modulation of T cell activation signals. We are currently investigating how 14-3-3 recruitment to SLP-76 affects immunological synapse formation and downstream signaling pathways.

Immunological synapse: a target for lymphotropic retroviruses.

We previously showed that intracellular endosomal trafficking is a key mechanism for molecular transport to the immunological synapse (Das et al, Immunity, 2004). Moreover, we showed that human immunodeficiency virus (HIV-1), by means of its protein Nef, impairs the endosomal vesicle transport of the protein tyrosine kinase Lck and of the T cell receptor to the immune synapse. This perturbs the formation and function of immunological synapses formed by infected T cells (Thoulouze et al, Immunity, 2006). Our recent data show that this mechanism targets only some particular molecules that traffic through endosomes leaving other molecules unperturbed. This underlines the importance and complexity of vesicle trafficking in the generation of immunological synapses and in T lymphocyte activation. Finally, we are studying how the human T cell leukemia virus type 1 (HTLV-1) subverts T cell biology to facilitate virus survival and cell-to-cell spread.

Keywords: Immunological synapse, T cell activation, T cell signaling, cytoskeleton, polarization, virological synapse, HIV, AIDS, intracellular traffic, endosomes

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  Publications

- Thoulouze M. I., Sol-Foulon N., Blanchet F., Dautry-Varsat A., Schwartz O., Alcover A. 2006. Human immunodefficiency virus (HIV-1) impairs the formation of the immunological synapse. Immunity. 24 :547-561. PMID: 16713973

- Schwartz O., Alcover A., Fackler O. T. 2007. Modulation of the immunological synapse : a key to HIV-1 pathogenesis ? Nature Rev Immunol. 7 : 310-317. PMID: 17380160

- Sol-Foulon N., Sourisseau, M., Porrot, F., Thoulouze, M. I., Trouillet, C., Nobile, C., Blanchet, F., Di Bartolo, V., Noraz, N., Taylor, N., Alcover, A., Hivroz, C., Schwartz, O. 2007. ZAP-70 kinase regulates HIV cell-to-cell spread and virological synapse formation. EMBO J. 26 : 512-526. PMID: 17215865

- Mugnier B, Nal B, Verthuy C, Boyer C, Lam D, Chasson L, Nieoullon V, Chazal G, Guo XJ, He HT, Rueff-Juy D, Alcover A, Ferrier P. 2008. Coronin-1A links cytoskeleton dynamics to TCR alpha beta-induced cell signaling. PloS One. e3467. PMID: 18941544

- Acuto O, Di Bartolo V, Michel F. 2008. Tailoring T-cell receptor signals by proximal negative feedback mechanisms.Nat Rev Immunol. 8:699-712. PMID: 18728635.





Activity Reports 2009 - Institut Pasteur
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