PhD PROPOSAL FOR THE PASTEUR-PARIS UNIVERSITY INTERNATIONAL PROGRAM

This project is funded by the EU-Marie Curie Initial Training Network Homin and displays particular features (see below and www homin-itn.eu)

 

Deadline for full application: January 15th, 2014

Interviews: February-March, 2014

Start of the Ph.D.: Before April 1st, 2014

 

 

Please fill in on the next page the summary of the PhD project(s) you propose.

 

Department: Immunology

 

Title of the PhD project: HIV-1 modulation of the T cell activation molecular machinery

Name of the lab: Lymphocyte Cell Biology

Head of the lab: Andrés Alcover

PhD advisor: Andrés Alcover

Email address: andres.alcover@pasteur.fr

Web site address of the lab: <http://www.pasteur.fr/research/biocelly>

Doctoral school affiliation and University: Ecole Doctorale Physiologie et Physiopathologie, Université Pierre et Marie Curie.

 

 

Presentation of the laboratory and its research topics:

 

The Lymphocyte Cell Biology Unit investigates the early stages of the adaptive immune response. In particular, we study the molecular mechanisms initiated upon T cell antigen recognition leading to the generation of immunological synapses, specialized cell-cell interfaces that control T cell activation and effector functions. We also investigate how the human immunodeficiency virus (HIV-1) subverts the molecular mechanisms that generate immunological synapses to modulate the activation capacity and the fate of infected T cells.

 

 

Description of the project:

Background and significance

Acquired immune responses are initiated by the activation of T lymphocytes having recognized antigens (i. e. bacterial, or viral processed protein fragments) displayed at the surface of antigen-presenting cells (APC). Antigen recognition triggers the profound reorganization of the T cell-APC contact site forming the so-called immunological synapse, a multitask cell interface, key for the control T of cell activation and effector functions, like polarized secretion of cytokines or cytotoxic granules. The Human Immunodeficiency Virus HIV-1 infects CD4 T lymphocytes inducing pleiotropic effects in these cells. We have shown that HIV-1 impairs the generation and function of immunological synapses. HIV-1 alters the intracellular traffic of the protein tyrosine kinase Lck, retaining it in endosomes and preventing its arrival to the immunological synapse, thus leading to impaired T cell receptor signal transduction. This allowed us to identify a novel mechanism targeted by HIV-1 to perturb T cell functions.

This PhD project will build on these findings, to get a deeper insight into the process of HIV-1 perturbation of the T cell activation machinery.

 

Main objectives of this project:

1) To get deeper insight into the molecular mechanisms subverted by HIV-1 that modulate the intracellular traffic of signaling molecules downstream the T cell antigen receptor, such as the tyrosine kinase Lck and the adapter LAT.

2) To investigate the consequences of the impairment of intracellular traffic in the generation of modified signaling pathways in infected T lymphocytes, by conventional methodologies, as well as by a proteomics study. This project will be conducted in collaboration with the company Photeomics (specialist in proteomics) thereby providing additional training experience in the industrial sector.

 

Experimental approaches: Cell biology, biochemical and molecular biology approaches, cutting edge microscopy and state-of-the-art proteomics.

 

References:

1. Soares H., Henriques R., Sachse M., Ventimiglia L., Alonso M.A., Zimmer C., Thoulouze M.I., Alcover A. Regulated vesicle fusion generates signaling nanoterritories that control T-cell activation at the immunological synapse. J. Exp. Med. 2013. 210 : 2415-2433.

2. Lasserre, R., Charrin, S., Cuche, C., Danckaert, A., Thoulouze, M. I., de Chaumont, F., Duong, T., Perrault, N., Varin-Blank, N., Olivo-Marin, J. C., Etienne-Manneville, S., Arpin, M., Di Bartolo, V., Alcover, A. Ezrin tunes T-cell activation by controlling Dlg1 and microtubule positioning at the immunological synapse. EMBO J. 2010. 29 : 2301-2314.

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

4. Soares H., Lasserre R., Alcover A. Orchestrating cytoskeleton and intracellular vesicle traffic to build functional immunological synapses. Immunol Rev 2013. 256: 118-132 (Review).

 

Keywords:

T cell activation, immunological synapse, HIV, T cell receptor, T cell signaling, intracellular traffic, endosomes

 

Expected profile of the candidate (optional):

 

Master diploma

Theoretical bases on Immunology and Cell biology. Practical bases in cell biology.

Available before April 1st 2014

 

Contact:

Andres Alcover: <andres.alcover@pasteur.fr>

 

Particular features: Funding immediately available from the European Union Marie Curie Actions Initial Training Network-Homin (www.homin-itn.eu). The successful candidate will belong to the Homin program and to the Pasteur Paris University International Doctoral Program.

Mis à jour le 02/12/2013