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MASTER des SCIENCES et DE LA SANTE
Mention INFECTIOLOGIE IMVI
SPÉCIALITÉ IMMUNOLOGIE
Renvoyer à Mme LARA
[email protected]
2 pages maximum
A renvoyer pour le 10 juin 2014
Proposition de Stage M2
Année Universitaire 2014 - 2015
1. Equipe d’Accueil de Master (EAM) : affiliation administrative et numéro de l’Unité :
INSERM U1151
Nom du Responsable du Laboratoire : Xavier Nassif
Nom du Responsable de l’Équipe : Peter van-Endert
Nom de l’équipe d’accueil : Présentation des antigènes: mécanismes et modulation par les
récepteurs Toll-like
Adresse : Hôpital Necker 149 rue de sèvres 75015 Paris
Responsable de l’encadrement : Bénédicte Manoury
Tél ; Fax et E-mail: 0144495379, 0144495382, [email protected]
2.
Parcours
! xImmunologie
_ Immunologie approfondie
_ Physiopathologie de la réponse immune
3. Thème du stage, titre et Description du sujet (1 page maximum) :
The role of UNC93B1 associated proteins in MHC I antigen cross presentation pathway
The innate immune system provides the first barrier against pathogens. At the steady state,
intracellular TLRs (TLR3, 7, 8 and 9) are retained in the ER together with a chaperone molecule,
UNC93B1. Upon stimulation, they relocate to the endo/lysosomal compartment, thus allowing
binding to their ligands and the recruitment of their adaptor molecules, MyD88 or TRIF. TLRs are
important molecules as they deliver signals allowing immature dendritic cells to switch to an
inflammatory phenotype that is capable of inducing adaptive immune responses. Mouse and
human genetics have identified UNC93B1, which encodes for a highly conserved 12-membrane
spanning molecule residing in the ER, as a key regulator in the transport of intracellular TLRs (7, 8
and 9). The 3d mutation (UNC93B1 mutation) results in inhibition of intracellular TLRs signaling
and exogenous antigen presentation (1). However, the exact role that UNC93B1 plays in antigen
presentation remains to be fully elucidated. We have shown that MHC I cross presentation of
exogenous antigen is drastically impaired in UNC93B1-mutated CD8+ and inflammatory dendritic
cells in vitro as well as in UNC93B1 mutated mice (3d mice) in vivo. Phagosomes are the
dedicated compartments for antigen cross presentation. Our data demonstrated that the fusion
with late endosomal compartments during phagosomal maturation is increased in UNC93B1mutated dendritic cells suggesting that ER-phagosome interaction may be altered. Moreover,
UNC93B1 mutation in dendritic cells remarkably reduced antigen degradation and export of
processed antigens into the cytoplasm. Using proteomic assays, we have identify four protein
whose expression is strongly down regulated in phagosomes from UNC93B1 mutated DCs. This
project is to address the role of these new molecules in the MHC I antigen cross presentation
pathway by using different technics such as biochemistry, molecular biology and
immunofluorescence.
1- Tabeta K, Hoebe K, Janssen EM, Du X, Georgel P, Crozat K, Mudd S, Mann N, Sovath S,
Goode J, Shamel L, Herskovits AA, Portnoy DA, Cooke M, Tarantino LM, Wiltshire T,
Steinberg BE, Grinstein S, Beutler B. The Unc93b1 mutation 3d disrupts exogenous
antigen presentation ans signaling vis Toll-like receptors 3, 7 and 9. Nat Immunol. 2006
Feb;7(2):156-64.
4. Composition de l’ Équipe d’Accueil
Nombre de scientifiques : 3
Enseignants Chercheurs :
Techniciens et Ingénieurs :
Postdoctorants :
Total :
...3.......
...2......
...2...
...7....
dont HDR :
.3.........
Total HDR :
....3......
Nombre d’Étudiants :
Master 2
1° année de thèse :
2° année de thèse :
3° année de thèse :
4° année de thèse :
Total Doctorants :
…3……
....0...
....1....
....1.....
....1....
....3....
5. Publications (5 parmi les plus significatives, au cours des quatre dernières années).
1- Benmohamed F, Medina, Wu YZ, Maschalidi S, Jouvion G, Guillemot L, Chignard M, Manoury
B, Touqui L. Toll-like receptor 9 deficiency protects mice against pseudomonas aeruginosa lung
infection. 2014 PLoS one Mar 4;9(3):e90466.
2- Apcher S, Millot G, Daskalogianni C, Sherl A, Manoury B, Fahraeus R. Translation of prespliced RNAs in the nuclear compartment generates peptides for the MHC class I pathway. 2013
Proc Natl Acad Sci U S A. Oct 29;110(44):17951-6.
3- Manoury B. Proteases : essential actors in processing antigens and intracellular Toll-like
receptors. 2013 Front Immunol Sep 24;4:299.
4- Maschalidi S, Hässler S, Blanc F, Sepulveda F, Tohme M, Chignard M, van Endert P, Si-Tahar
M, Descamps D and Manoury B. Asparagine Endopeptidase Controls Anti-Influenza Virus Immune
Responses through TLR7 Activation. 2012 PLoS Pathog. Aug;8(8):e1002841.
5.- Descamps D, Le Gars M, Balloy V, Barbier D, Maschalidi S, Chignard M, Ramphal R, Manoury
B1, Sallenave JM1. TLR5 activation, IL-1b signaling and asparagine endopeptidase activity: a new
pathway for alveolar macrophage phagocytosis and bacterial killing. 2012 Proc Natl Acad Sci U S
A 109:1619-24. 1Corresponding authors.
Appartenance à L’Ecole Doctorale
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