Antiviral Cell Immunology - URA CNRS 1961  


  HEADLEMONNIER François / flemonn@pasteur.fr
  MEMBERSPermanent scientists : Dr HUETZ François / Dr LONE Yu chun / Dr ROTH Claude
Temporary scientists : BOUZIAT Romain / KRIDANE Hédia / Dr LAIKA Taghrid / RIOU Sylvain / Dr SALMON Jerôme
Research Engineer : BAWA Olivia / Secretary : DETCHEPARE Christine


  Annual Report

1. HLA transgenic H-2 KO strains of mice for vaccine research (O. Bawa, R. Bouziat, J. Salmon, YC. Lone)

The following strains, homozygous for all the listed characters, are available: HLA-A02.01, HLA-DR1 (or -DR3, or -DQ8) H-2 class I/class II KO ; HLA-DP4, human CD4, H-2 class II KO, mouse CD4 KO. These mice and 2 additional strains (HLA-A24, H-2 class I KO and HLA-A3.1, H-2 class I KO) have been used to identify new Hepatitis B and HIV-1-derived T cell epitopes and to compare their intrinsic immunogenicity. Structurally conserved epitopes of proven immunogenicity have been (HLA-A2, -B7) or will be (HLA-A24, -A3) inserted in polyepitope constructs that should be of interest for a large fraction of individuals in human populations.

These strains of mice have also been used to identify epitopic peptides in the 3 sub-types of Dengue virus and presented by the the HLA-A02.01, -B07.02, -A24.02, and HLA-DR1 molecules.

Collaborators: M.-L. Michel, Département de Virologie; P. Charneau, Unité de Virologie Moléculaire et Vectorologie; Thomas J. August, Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medecine, Baltimore.

2. Humanized animal model for type I diabetis (T. Laika).

This work is headed on a collaborative basis by Pr C. Boitard, INSERM U561, Paris. Five peptides from human and mouse preproinsulins have been identified that stimulate HLA-A2-restricted cytolytic responses in HLA-A2 transgenic mice and it has been established that these peptides are efficiently naturally processed. Four preproinsulin peptides have been shown to stimulate HLA-DQ8-restricted T cell proliferative responses.

HLA-A2, HLA-DQ8 H-2 class I class II KO mice are currently crossed with human preproinsulin transgenic, mouse preproinsulin 1 and 2 KO mice and the experimental conditions that could break tolerance to preproinsulin are explored.

3. T cell recognition of Hfe molecule (H. Kridane, F. Huetz and F. Lemonnier).

Hfe, a MHC class Ib molecule that has no antigen-presenting function (its peptide groove is narrow and empty) regulates iron metabolism. Nevertheless, Hfe stimulates directly cytolytic responses mediated by αβ TCR CD8+ T cells. We are exploring the physiological relevance of this interface between the immune system and iron metabolism and the possibility that Hfe could be, on its own, a histocompatibility molecule. Transgenic mice expressing a Hfe-specific TCR have been created and recently performed experiments established that tolerance toward Hfe results from the thymic delection of Hfe-reactive CD8+ T cells..

Collaborators: P. Rohrlich, R. Boucherma, INSERM U645, Besançon, France ; K.C. Garcia, Stanford, CA ; J. Kanellopoulos, UMR 8619, CNRS, Orsay, France.

4. Natural Killer (NK) cell differentiation (S. Riou and C. Roth).

This work has established that the terminal differentiation of NK cells (an essential cellular component of innate immunity) is dependent on signals transmited by Tyrosine kinase receptors of the Tyro 3 family (Tyro 3, mer, Axl). The activation pathway(s) responsible for this terminal differentiation are studied.

Collaborators: D. Raulet, and G. Lemke, Berkeley, CA.

Keywords: Hfe, VIH1, vaccine, transgenesis



  Publications

Cardinaud S, Moris A, Fevrier M, Rohrlich PS, Weiss L, Langlade-Demoyen P, Lemonnier FA, Schwartz O, Habel A. Identification of Cryptic MHC I-restricted Epitopes Encoded by HIV-1 Alternative Reading Frames. J Exp Med. 2004. 199 : 1053-1063.

Rohrlich PS, Fazilleau N, Ginhoux F, Firat H, Michel F, Cochet M, Laham N, Roth MP, Pascolo S, Nato F, Coppin H, Charneau P, Danos O, Acuto O, Ehrlich R, Kanellopoulos J, Lemonnier FA. Direct recognition by {alpha}{beta} cytolytic T cells of Hfe, a MHC class Ib molecule without antigen-presenting function. Proc. Natl. Acad. Sci. USA. 2005. 102:12855-12860.

Caraux A, Lu Q, Fernandez N, Riou S, Di Santo JP, Raulet DH, Lemke G, Roth C. Natural killer cell differentiation driven by Tyro3 receptor tyrosine kinases. Nat. Immunol. 2006. 7 : 747-54.

Pajot A, Schnuriger A, Moris A, Rodallec A, Ojcius DM, Autran B, Lemonnier FA, Lone YC. The Th1 immune response against HIV-1 Gag p24-derived peptides in mice expressing HL-A02.01 abd HLA-DR1. Eur J Immunol. 2007 Sep ; 37 (9) : 2635-44

Lim A, Lemercier B, Wertz X, Pottier SL, Huetz F, Kourilsky P. Many human peripheral VH5-expressing IgM+ B cells display a unique heavy-chain rearrangement. Int Immunol. 2008 Jan;20(1):105-16. Epub 2007 Nov 20.PMID: 18032374





Activity Reports 2007 - Institut Pasteur
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