J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/06/2043/09 $2.00
Volume 185, Number 12, June 16, 1997 2043-2051

HLA-A2.1-restricted Education and Cytolytic Activity of CD8⁺ T Lymphocytes from 2 Microglobulin (2m) HLA-A2.1 Monochain Transgenic H-2D^b 2m Double Knockout Mice

By Steve Pascolo,^* Nathalie Bervas,^* Jan M. Ure, Austin G. Smith, François A. Lemonnier,^* and Béatrice Pérarnau^*

From the ^* Institut Pasteur, Département SIDA-Rétrovirus, Unité d'Immunité Cellulaire Antivirale, 75724 Paris Cedex 15, France; and  Gene Targeting Laboratory, Centre for Genome Research, University of Edinburgh, Edinburgh EH9 3JQ, United Kingdom

Three different HLA-A2.1 monochains were engineered in which either the human or mouse 2-microglobulin (2m) is covalently linked to the NH₂ terminus of the heavy chain by a 15- amino acid long peptide: HHH, entirely human, HHD, with the mouse H-2D^b 3, transmembrane, and cytoplasmic domains, and MHD, homologous to HHD but linked to the mouse 2m^b. The cell surface expression and immunological capacities of the three monochains were compared with transfected cells, and the selected HHD construct was introduced by transgenesis in H-2D^b/ 2m^/ double knockout mice. Expression of this monochain restores a sizable peripheral CD8⁺ T cell repertoire essentially educated on the transgenic human molecule. Consequently, infected HHD, H-2D^b/ 2m^/ mice generate only HLA-A2.1-restricted CD8⁺ CTL responses against influenza A and vaccinia viruses. Interestingly, the CTL response to influenza A virus is mostly, if not exclusively, directed to the 58-66 matrix peptide which is the HLA-A2.1-restricted immunodominant epitope in humans. Such mice might constitute a versatile animal model for the study of HLA-A2.1-restricted CTL responses of vaccine interest.

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• Cohen, C. J., Hoffmann, N., Farago, M., Hoogenboom, H. R., Eisenbach, L., Reiter, Y. (2002). Direct Detection and Quantitation of a Distinct T-Cell Epitope Derived from Tumor-specific Epithelial Cell-associated Mucin Using Human Recombinant Antibodies Endowed with the Antigen-specific, Major Histocompatibility Complex-restricted Specificity of T Cells. Cancer Res. 62: 5835-5844 [Abstract] [Full Text]  
• Denkberg, G., Klechevsky, E., Reiter, Y. (2002). Modification of a Tumor-Derived Peptide at an HLA-A2 Anchor Residue Can Alter the Conformation of the MHC-Peptide Complex: Probing with TCR-Like Recombinant Antibodies. J. Immunol. 169: 4399-4407 [Abstract] [Full Text]  
• Boissonnas, A., Bonduelle, O., Antzack, A., Lone, Y.-C., Gache, C., Debre, P., Autran, B., Combadiere, B. (2002). In Vivo Priming Of HIV-Specific CTLs Determines Selective Cross-Reactive Immune Responses Against Poorly Immunogenic HIV-Natural Variants. J. Immunol. 169: 3694-3699 [Abstract] [Full Text]  
• Hernandez, J., Garcia-Pons, F., Lone, Y. C., Firat, H., Schmidt, J. D., Langlade-Demoyen, P., Zanetti, M. (2002). Identification of a human telomerase reverse transcriptase peptide of low affinity for HLA A2.1 that induces cytotoxic T lymphocytes and mediates lysis of tumor cells. Proc. Natl. Acad. Sci. USA 99: 12275-12280 [Abstract] [Full Text]  
• Firat, H., Cochet, M., Rohrlich, P.-S., Garcia-Pons, F., Darche, S., Danos, O., Lemonnier, F. A., Langlade-Demoyen, P. (2002). Comparative analysis of the CD8+ T cell repertoires of H-2 class I wild-type/HLA-A2.1 and H-2 class I knockout/HLA-A2.1 transgenic mice. Int Immunol 14: 925-934 [Abstract] [Full Text]  
• Graff-Dubois, S., Faure, O., Gross, D.-A., Alves, P., Scardino, A., Chouaib, S., Lemonnier, F. A., Kosmatopoulos, K. (2002). Generation of CTL Recognizing an HLA-A*0201-Restricted Epitope Shared by MAGE-A1, -A2, -A3, -A4, -A6, -A10, and -A12 Tumor Antigens: Implication in a Broad-Spectrum Tumor Immunotherapy. J. Immunol. 169: 575-580 [Abstract] [Full Text]  
• Lev, A., Denkberg, G., Cohen, C. J., Tzukerman, M., Skorecki, K. L., Chames, P., Hoogenboom, H. R., Reiter, Y. (2002). Isolation and Characterization of Human Recombinant Antibodies Endowed with the Antigen-specific, Major Histocompatibility Complex-restricted Specificity of T Cells Directed toward the Widely Expressed Tumor T-cell Epitopes of the Telomerase Catalytic Subunit. Cancer Res. 62: 3184-3194 [Abstract] [Full Text]  
• Scardino, A., Gross, D.-A., Alves, P., Schultze, J. L., Graff-Dubois, S., Faure, O., Tourdot, S., Chouaib, S., Nadler, L. M., Lemonnier, F. A., Vonderheide, R. H., Cardoso, A. A., Kosmatopoulos, K. (2002). HER-2/neu and hTERT Cryptic Epitopes as Novel Targets for Broad Spectrum Tumor Immunotherapy. J. Immunol. 168: 5900-5906 [Abstract] [Full Text]  
• Passoni, L., Scardino, A., Bertazzoli, C., Gallo, B., Coluccia, A. M. L., Lemonnier, F. A., Kosmatopoulos, K., Gambacorti-Passerini, C. (2002). ALK as a novel lymphoma-associated tumor antigen: identification of 2 HLA-A2.1-restricted CD8+ T-cell epitopes. Blood 99: 2100-2106 [Abstract] [Full Text]  
• Brinster, C., Chen, M., Boucreux, D., Paranhos-Baccala, G., Liljestrom, P., Lemmonier, F., Inchauspe, G. (2002). Hepatitis C virus non-structural protein 3-specific cellular immune responses following single or combined immunization with DNA or recombinant Semliki Forest virus particles. J. Gen. Virol. 83: 369-381 [Abstract] [Full Text]  
• Miconnet, I., Koenig, S., Speiser, D., Krieg, A., Guillaume, P., Cerottini, J.-C., Romero, P. (2002). CpG Are Efficient Adjuvants for Specific CTL Induction Against Tumor Antigen-Derived Peptide. J. Immunol. 168: 1212-1218 [Abstract] [Full Text]  
• Pascolo, S., Schirle, M., Gückel, B., Dumrese, T., Stumm, S., Kayser, S., Moris, A., Wallwiener, D., Rammensee, H.-G., Stevanovic, S. (2001). A MAGE-A1 HLA-A*0201 Epitope Identified by Mass Spectrometry. Cancer Res. 61: 4072-4077 [Abstract] [Full Text]  
• Karadimitris, A., Gadola, S., Altamirano, M., Brown, D., Woolfson, A., Klenerman, P., Chen, J.-L., Koezuka, Y., Roberts, I. A. G., Price, D. A., Dusheiko, G., Milstein, C., Fersht, A., Luzzatto, L., Cerundolo, V. (2001). From the Cover: Human CD1d-glycolipid tetramers generated by in vitro oxidative refolding chromatography. Proc. Natl. Acad. Sci. USA 98: 3294-3298 [Abstract] [Full Text]  
• Loirat, D., Lemonnier, F. A., Michel, M.-L. (2000). Multiepitopic HLA-A*0201-Restricted Immune Response Against Hepatitis B Surface Antigen After DNA-Based Immunization. J. Immunol. 165: 4748-4755 [Abstract] [Full Text]  
• Borenstein, S. H., Graham, J., Zhang, X.-L., Chamberlain, J. W. (2000). CD8+ T Cells Are Necessary for Recognition of Allelic, But Not Locus-Mismatched or Xeno-, HLA Class I Transplantation Antigens. J. Immunol. 165: 2341-2353 [Abstract] [Full Text]  
• Azoulay-Cayla, A., Dethlefs, S., Pérarnau, B., Larsson-Sciard, E.-L., Lemonnier, F. A., Brahic, M., Bureau, J.-F. (2000). H-2Db-/- Mice Are Susceptible to Persistent Infection by Theiler's Virus. J. Virol. 74: 5470-5476 [Abstract] [Full Text]  
• Bullock, T. N. J., Colella, T. A., Engelhard, V. H. (2000). The Density of Peptides Displayed by Dendritic Cells Affects Immune Responses to Human Tyrosinase and gp100 in HLA-A2 Transgenic Mice. J. Immunol. 164: 2354-2361 [Abstract] [Full Text]  
• Su, R.-C., Kung, S. K.-P., Silver, E. T., Lemieux, S., Kane, K. P., Miller, R. G. (1999). Ly-49CB6 NK Inhibitory Receptor Recognizes Peptide-Receptive H-2Kb 1. J. Immunol. 163: 5319-5330 [Abstract] [Full Text]  
• Murali-Krishna, K., Lau, L. L., Sambhara, S., Lemonnier, F., Altman, J., Ahmed, R. (1999). Persistence of Memory CD8 T Cells in MHC Class I-Deficient Mice. Science 286: 1377-1381 [Abstract] [Full Text]  
• Lauvau, G., Kakimi, K., Niedermann, G., Ostankovitch, M., Yotnda, P., Firat, H., Chisari, F. V., van Endert, P. M. (1999). Human Transporters Associated with Antigen Processing (TAPs) Select Epitope Precursor Peptides for Processing in the Endoplasmic Reticulum and Presentation to T Cells. JEM 190: 1227-1240 [Abstract] [Full Text]  
• Chung, D. H., Dorfman, J., Plaksin, D., Natarajan, K., Belyakov, I. M., Hunziker, R., Berzofsky, J. A., Yokoyama, W. M., Mage, M. G., Margulies, D. H. (1999). NK and CTL Recognition of a Single Chain H-2Dd Molecule: Distinct Sites of H-2Dd Interact with NK and TCR. J. Immunol. 163: 3699-3708 [Abstract] [Full Text]  
• Mateo, L., Gardner, J., Chen, Q., Schmidt, C., Down, M., Elliott, S. L., Pye, S. J., Firat, H., Lemonnier, F. A., Cebon, J., Suhrbier, A. (1999). An HLA-A2 Polyepitope Vaccine for Melanoma Immunotherapy. J. Immunol. 163: 4058-4063 [Abstract] [Full Text]  
• Ureta-Vidal, A., Firat, H., Perarnau, B., Lemonnier, F. A. (1999). Phenotypical and Functional Characterization of the CD8+ T Cell Repertoire of HLA-A2.1 Transgenic, H-2Kb{degrees}Db{degrees} Double Knockout Mice. J. Immunol. 163: 2555-2560 [Abstract] [Full Text]  
• Woodberry, T., Gardner, J., Mateo, L., Eisen, D., Medveczky, J., Ramshaw, I. A., Thomson, S. A., Ffrench, R. A., Elliott, S. L., Firat, H., Lemonnier, F. A., Suhrbier, A. (1999). Immunogenicity of a Human Immunodeficiency Virus (HIV) Polytope Vaccine Containing Multiple HLA A2 HIV CD8+ Cytotoxic T-Cell Epitopes. J. Virol. 73: 5320-5325 [Abstract] [Full Text]  
• Men, Y., Miconnet, I., Valmori, D., Rimoldi, D., Cerottini, J.-C., Romero, P. (1999). Assessment of Immunogenicity of Human Melan-A Peptide Analogues in HLA-A*0201/Kb Transgenic Mice. J. Immunol. 162: 3566-3573 [Abstract] [Full Text]  
• Vugmeyster, Y., Glas, R., Perarnau, B., Lemonnier, F. A., Eisen, H., Ploegh, H. (1998). Major histocompatibility complex (MHC) class I KbDb -/- deficient mice possess functional CD8+ T cells and natural killer cells. Proc. Natl. Acad. Sci. USA 95: 12492-12497 [Abstract] [Full Text]  
• Miyazaki, T., Lemonnier, F. A. (1998). Modulation of  Thymic Selection by Expression of an Immediate-early Gene, Early Growth Response 1 (Egr-1). JEM 188: 715-723 [Abstract] [Full Text]  
• Tanchot, C., Lemonnier, F. A., Pérarnau, B., Freitas, A. A., Rocha, B. (1997). Differential Requirements for Survival and Proliferation of CD8 Naïve or Memory T Cells. Science 276: 2057-2062 [Abstract] [Full Text]  
• Minev, B., Hipp, J., Firat, H., Schmidt, J. D., Langlade-Demoyen, P., Zanetti, M. (2000). Cytotoxic T cell immunity against telomerase reverse transcriptase in humans. Proc. Natl. Acad. Sci. USA 97: 4796-4801 [Abstract] [Full Text]  

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