|Lymphocyte Cell Biology - CNRS URA 1961|
|HEAD||Dr Andrés ALCOVER / firstname.lastname@example.org|
|MEMBERS||Dr Vincenzo Di BARTOLO / Dr Maria-Isabel THOULOUZE
Dr Rémi LASSERRE / Dr Helena MARTINS-SOARES
Ana-Monica PAIS-CORREIA / Valentina ROBBIATI
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. These organized cellular contacts ensure the communication between T cells and antigen presenting cells, being named immunological synapses.
We investigate the molecular mechanisms that generate immunological synapses and their role in T cell activation. We also study how lymphotropic retroviruses subvert these mechanisms to modulate T cell responses and to spread 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). We recently unveiled 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 described a novel interaction between the scaffold protein SLP-76 and members of the 14-3-3 protein family, which is important for the negative modulation of T cell activation signals (Di Bartolo et al., J Exp Med, 2007). We are currently investigating how Ezrin and SLP-76 modulate immunological synapse formation therefore tuning T cell receptor signaling pathways.
Immunological synapse: a target for lymphotropic retroviruses.
We had shown before that polarized intracellular traffic of endosomes is crucial for molecular transport to the immunological synapse (Das et al, Immunity, 2004). We also showed that the human immunodeficiency virus (HIV-1) inhibits the endosomal transport of the protein tyrosine kinase Lck and of the T cell receptor to the T cell-antigen presenting cell interface, impairing the formation and function of immunological synapses (Thoulouze et al, Immunity, 2006). Our recent data reveal that intracellular vesicle traffic to the immunological synapse is tightly regulated. HIV-1 specifically targets the vesicular traffic of some particular signaling molecules leaving others unperturbed.
We have also studied how the human T cell leukemia virus type 1 (HTLV-1) utilizes polarized T cell contacts to efficiently spread from cell to cell. We have unveiled a novel mechanism involving the generation of biofilm-like extracellular viral assemblies containing viral particles embedded in a mesh of carbohydrate-rich extracellular matrix and linker proteins. These viral assemblies remain attached to the surface of virus-producing cells, and can rapidly adhere to, and infect other cells. Their protein composition, their structure and function are reminiscent of bacterial biofilms. Removal of "viral biofilms" from the surface of HTLV-1-producing lymphocytes strongly inhibits their capacity to infect other cells. "Viral biofilms" might be generated by other viruses, and represent an interesting target for future anti-viral therapies (Pais-Correia et al, Nat Med, 2010).
Keywords: Immunological synapse, T cell activation, T cell signaling, cytoskeleton, polarization, intracellular traffic, endosomes, virological synapse, HIV, AIDS, HTLV, extracellular matrix, viral biofilms
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
Di Bartolo, V., Montagne, B., Salek, M., Jungwirth, B., Carrette, F., Fourtane, J., Sol-Foulon, N., Michel, F., Schwartz, O., Lehmann, W. D., and Acuto, O. 2007 A novel pathway down-modulating T cell activation involves HPK-1-dependent recruitment of 14-3-3 proteins on SLP-76. J Exp Med. 204: 681-691. PMID: 17353368.
Schwartz O., Alcover A., Fackler O. T. 2007. Modulation of the immunological synapse : a key to HIV-1 pathogenesis ? Nat Rev Immunol. 7 : 310-317. PMID: 17380160
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.
Pais-Correia A. M., Sachse M., Guadagnini S., Robbiati V., Lasserre R., Gessain A., Gout O., Alcover A., Thoulouze M. I. 2010. Biofilm-like extracellular viral assemblies mediate HTLV-1 cell-to-cell transmission at virological synapses. Nat Med. 16: 83-9. Epub 2009 Dec 20. PMID: 20023636.
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