Littman Laboratory: T Cell Development and Retroviral Pathogenesis

Mick Menager

Mickaël Menager
Embo Fellow
Ph.D University of Paris VII, France
INSERM U768, Necker’s hospital, 2008

During my PhD, I studied T lymphocyte homeostasis and cytotoxic function in Pr Alain Fischer’s laboratory, in Dr Genevieve de Saint Basile’s team . (Necker’s hospital, Paris, France). My particular subject was to investigate function(s) and molecular interaction(s) of hMunc13-4 and Rab27a, two critical effectors of the cytotoxic granule secretory pathway, involved in an uncontrolled lymphoproliferative disease, called the Haemophagocytic Syndrome.

Using confocal microscopy experiments and biochemistry we were able to demonstrate that the granule-dependent cytotoxic function of lymphocytes requires the cooperation of two types of organelles, the lytic granule and an endosomal-like “exocytic vesicle”. In a first step of the secretory pathway, hMunc13-4, independently of Rab27a, mediates assembly of recycling and late endosomal structures to constitute a pool of endosomal vesicles engaged into the regulated exocytic pathway. Cytotoxic-target cell recognition induces a rapid polarization of both types of organelles, which overlap and likely fuse at the cell-cell contact. In addition, hMunc13-4 has been identified as one of the effectors of Rab27a, potentially connecting granule docking to granule priming at the Immunological Synapse. We have also shown that Rab27a recruits a previously unknown hematopoietic form of Slp2a (Slp2a-hem) on vesicular structures in peripheral CTLs. Following CTL-target cell conjugate formation, the Slp2a-hem/Rab27a complex colocalizes with perforin-containing granules at the immunological synapse, where it binds to the plasma membrane through its C2 domains.

In Dan Littman’s laboratory, I will try to focus on several aspects of the cellular Biology of HIV trafficking in T cells and dendritic cells.

Publications

Mickaël M. Ménager, Gaël Ménasché (co-authors), Juliette M. Lefebvre, Einat Deutsch, Rafika Athman, Nathalie Lambert, Nizar Mahlaoui, Magali Court, Jérôme Garin, Alain Fischer and Geneviève de Saint Basile. A newly identified isoform of Slp2a associates with Rab27a in cytotoxic T cells and participates to cytotoxic granule secretion. Blood, accepted

Mickaël M. Ménager, Gaël Ménasché, Maryse Romao, Perrine Knapnougel, Chen-Hsuan Ho, Mériem Garfa, Graça Raposo, Jérôme Feldmann, Alain Fischer and Geneviève de Saint Basile .Secretory cytotoxic granule maturation and exocytosis require the effector protein hMunc13-4. Nat Immunology, (Vol.8, No.3.pp257-267 (2007)).

Mateo V, Ménager M, de Saint-Basile G, Stolzenberg MC, Roquelaure B, André N, Florkin B, le Deist F, Picard C, Fischer A, Rieux-Laucat F. Perforin-dependent apoptosis functionally compensates Fas deficiency in activation-induced cell death of human T lymphocytes. Blood. 2007 Dec 15;110(13):4285-92. Epub 2007 Aug 27.

Mickaël M. Ménager and Geneviève de Saint Basile. Secretory cytotoxic granule maturation is required to their lytic contents excretion. Med Sci (Paris). 2007 May;23(5):473-4. French

Menasche G, Ménager M, Le Deist F, Fischer A, de Saint Basile G. Defect in lytic granule exocytosis: several causes, a same effect. Med Sci (Paris). 2006 Aug-Sep;22(8-9):733-8. French .