Antiviral Cell Immunology - URA CNRS 1961  


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


  Annual Report

1. HLA transgenic H-2 KO strains of mice for vaccine research (R. Bouziat, F. Huetz)

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 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. HLA-A02.01 transgenic H-2 class I KO mice have been used to analyse by quantitative RT-PCR the CD8+ T cell TCR repertoire educated at the thymus level or mobilized in the periphery by the sole HLA-A02.01 molecule. A preferential usage of the AV9 segment family has been documented in both cases, suggesting a strong affinity of the complementary determining region 1 and 2 for the α1 2 helices of HLA-A02.01. Detailed analysis of this phenomenon might shed light on acute allo reactions observed in certain HLA class I or class II mismatches in human clinic.

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 ; A. Venet, Inserm U802, Le Kremlin Bicêtre ; A. Lim, Développement des Lymphocytes.

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 have been crossed with human preproinsulin transgenic, mouse preproinsulin 1 and 2 KO mice and the experimental conditions that could break in these mice 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. Transgenic mice expressing a HFE-specific TCR have been created. Using these mice we have documented the fact that HFE behaves as a skin associated autonomous histocompatibility antigen not only for Hfe KO mice but also for mice carrying the C 282  Y mutation that destabilizes the whole HFE molecule an is responsible in humans for a large majority of hereditary hemochromatosis.

Collaborators: P. Rohrlich, R. Boucherma, INSERM U645, Besançon, France ; J. Kanellopoulos, UMR 8619, CNRS, Orsay, France ; N. Andrews, Duke University, Durham, NC ; F. Langa-Vives, Centre d’Ingénierie Murine ; L. Fiette, Unité de Recherche et d'Expertise Histotechnologie et Pathologie.

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 transmitted by Receptor Tyrosine Kinase of the Tyro3 family (Tyro3, Axl and Mer). Interactions of Tyro3 receptors on the immature NK cell with Tyro3 ligands on bone marrow stromal cells are required for complete NK cell development in vitro and in vivo. We have also recently identified in the bone marrow and spleen of the adult mice a rare population of mature B cells that contains NK cell-specified precursors. The functions of this population are currently studied.

Collaborators: D. Raulet, U.C.Berkeley, CA ; G. Lemke, Salk Institute, La Jolla, CA ; E. Vivier, L. Chiossone, T. Walzer, CIML, Marseille ; C. Mautaudoin, A. Thiriot and A. Freitas, Institut Pasteur, Paris).



  Publications

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

Toma A, Laïka T, Haddouk S, Luce S, Briand JP, Camoin L, Connan F, Lambert M, Caillat-Zucman S, Carel JC, Muller S, Choppin J, Lemonnier F, Boitard C. Recognition of human proinsulin leader sequence by class I-restricted T cells in HLA-A*0201 transgenic mice and in human type 1 diabetes. Diabetes. 2008 Nov 14.





Activity Reports 2009 - Institut Pasteur
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