Journal of Experimental Medicine, Vol 180, 1901-1910, Copyright © 1994 by Rockefeller University Press

ARTICLES

Thymic selection and adaptability of cytotoxic T lymphocyte responses in transgenic mice expressing a viral protein in the thymus

MG von Herrath, J Dockter, M Nerenberg, JE Gairin and MB Oldstone
Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037.

Upon primary challenge with lymphocytic choriomeningitis virus (LCMV), H-2d (BALB/cByJ) mice mount a cytotoxic T lymphocyte (CTL) response to a single immunodominant domain of the viral nucleoprotein (NP) but no detectable response to the viral glycoprotein (GP). To manipulate this CTL response, the viral NP gene was expressed in the thymus and peripheral T lymphocytes using the murine Thy1.2 promoter. As a result, such Thy1.2-NP (H-2d) transgenic (tg) mice deleted their high-affinity anti-LCMV-NP CTL, but generated equal numbers of lower-affinity NP CTL. Further, they made an alternative anti-LCMV-GP CTL response that is not normally found in non-tg mice indicating a hierarchial control of the CTL response. Unlike the H-2d mice, H-2b (C57Bl/6J) mice normally mount a CTL response to both LCMV-GP and -NP. When the LCMV-NP was expressed using the Thy1.2 promoter in these H-2b mice, the LCMV-NP-specific CTL response was completely aborted and no CTL to new, alternative viral epitopes were generated. Dilutions of H-2b or H-2d NP peptides indicated that 3-4 logs less H-2b NP peptide was required to sensitize syngeneic target cells for CTL-specific lysis, suggesting that the differing affinities of H-2b and H-2d major histocompatibility complex molecules for their peptides likely account for the total removal of NP CTL in the H-2b mice but only partial removal in H-2d mice made to express thymic NP. Thymic grafting experiments done with thymi from newborn Thy1.2-NP tg mice show that selection processes studied in this model are of central (thymic) origin and are not caused by Thy1.2- positive LCMV-NP-expressing T lymphocytes in the periphery.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Liu, J., Ewald, B. A., Lynch, D. M., Nanda, A., Sumida, S. M., Barouch, D. H. (2006). Modulation of DNA Vaccine-Elicited CD8+ T-Lymphocyte Epitope Immunodominance Hierarchies. J. Virol. 80: 11991-11997 [Abstract] [Full Text]  
• Newberg, M. H., McEvers, K. J., Gorgone, D. A., Lifton, M. A., Baumeister, S. H. C., Veazey, R. S., Schmitz, J. E., Letvin, N. L. (2006). Immunodomination in the Evolution of Dominant Epitope-Specific CD8+ T Lymphocyte Responses in Simian Immunodeficiency Virus-Infected Rhesus Monkeys. J. Immunol. 176: 319-328 [Abstract] [Full Text]  
• Rhode, A., Pauza, M. E., Barral, A. M., Rodrigo, E., Oldstone, M. B. A., von Herrath, M. G., Christen, U. (2005). Islet-Specific Expression of CXCL10 Causes Spontaneous Islet Infiltration and Accelerates Diabetes Development. J. Immunol. 175: 3516-3524 [Abstract] [Full Text]  
• Sinha, P., Chi, H. H., Kim, H. R., Clausen, B. E., Pederson, B., Sercarz, E. E., Forster, I., Moudgil, K. D. (2004). Mouse Lysozyme-M Knockout Mice Reveal How the Self-Determinant Hierarchy Shapes the T Cell Repertoire against This Circulating Self Antigen in Wild-Type Mice. J. Immunol. 173: 1763-1771 [Abstract] [Full Text]  
• Slifka, M. K., Blattman, J. N., Sourdive, D. J. D., Liu, F., Huffman, D. L., Wolfe, T., Hughes, A., Oldstone, M. B. A., Ahmed, R., von Herrath, M. G. (2003). Preferential Escape of Subdominant CD8+ T Cells During Negative Selection Results in an Altered Antiviral T Cell Hierarchy. J. Immunol. 170: 1231-1239 [Abstract] [Full Text]  
• Pien, G. C., Nguyen, K. B., Malmgaard, L., Satoskar, A. R., Biron, C. A. (2002). A Unique Mechanism for Innate Cytokine Promotion of T Cell Responses to Viral Infections. J. Immunol. 169: 5827-5837 [Abstract] [Full Text]  
• Wolfe, T., Asseman, C., Hughes, A., Matsue, H., Takashima, A., von Herrath, M. G. (2002). Reduction of Antiviral CD8 Lymphocytes In Vivo with Dendritic Cells Expressing Fas Ligand--Increased Survival of Viral (Lymphocytic Choriomeningitis Virus) Central Nervous System Infection. J. Immunol. 169: 4867-4872 [Abstract] [Full Text]  
• Oldstone, M. B. A., Race, R., Thomas, D., Lewicki, H., Homann, D., Smelt, S., Holz, A., Koni, P., Lo, D., Chesebro, B., Flavell, R. (2002). Lymphotoxin-{alpha}- and Lymphotoxin-{beta}-Deficient Mice Differ in Susceptibility to Scrapie: Evidence against Dendritic Cell Involvement in Neuroinvasion. J. Virol. 76: 4357-4363 [Abstract] [Full Text]  
• von Herrath, M. G., Wolfe, T., Mohrle, U., Coon, B., Hughes, A. (2001). Protection From Type 1 Diabetes in the Face of High Levels of Activated Autoaggressive Lymphocytes in a Viral Transgenic Mouse Model Crossed to the SV129 Strain. Diabetes 50: 2700-2708 [Abstract] [Full Text]  
• Sette, A. D., Oseroff, C., Sidney, J., Alexander, J., Chesnut, R. W., Kakimi, K., Guidotti, L. G., Chisari, F. V. (2001). Overcoming T Cell Tolerance to the Hepatitis B Virus Surface Antigen in Hepatitis B Virus-Transgenic Mice. J. Immunol. 166: 1389-1397 [Abstract] [Full Text]  
• Sevilla, N., Homann, D., von Herrath, M., Rodriguez, F., Harkins, S., Whitton, J. L., Oldstone, M. B. A. (2000). Virus-Induced Diabetes in a Transgenic Model: Role of Cross-Reacting Viruses and Quantitation of Effector T Cells Needed To Cause Disease. J. Virol. 74: 3284-3292 [Abstract] [Full Text]  
• Holz, A., Bot, A., Coon, B., Wolfe, T., Grusby, M. J., von Herrath, M. G. (1999). Disruption of the STAT4 Signaling Pathway Protects from Autoimmune Diabetes While Retaining Antiviral Immune Competence. J. Immunol. 163: 5374-5382 [Abstract] [Full Text]  
• von Herrath, M., Coon, B., Homann, D., Wolfe, T., Guidotti, L. G. (1999). Thymic Tolerance to Only One Viral Protein Reduces Lymphocytic Choriomeningitis Virus-Induced Immunopathology and Increases Survival in Perforin-Deficient Mice. J. Virol. 73: 5918-5925 [Abstract] [Full Text]  
• Mariathasan, S., Bachmann, M. F., Bouchard, D., Ohteki, T., Ohashi, P. S. (1998). Degree of TCR Internalization and Ca2+ Flux Correlates with Thymocyte Selection. J. Immunol. 161: 6030-6037 [Abstract] [Full Text]  
• Oldstone, M. B. A. (1998). Molecular mimicry and immune-mediated diseases. FASEB J. 12: 1255-1265 [Abstract] [Full Text]  
• Weidt, G., Utermohlen, O., Heukeshoven, J., Lehmann-Grube, F., Deppert, W. (1998). Relationship Among Immunodominance of Single CD8+ T Cell Epitopes, Virus Load, and Kinetics of Primary Antiviral CTL Response. J. Immunol. 160: 2923-2931 [Abstract] [Full Text]  
• von Herrath, M. G., Efrat, S., Oldstone, M. B. A., Horwitz, M. S. (1997). Expression of adenoviral E3 transgenes in beta  cells prevents autoimmune diabetes. Proc. Natl. Acad. Sci. USA 94: 9808-9813 [Abstract] [Full Text]  
• Balasa, B., Deng, C., Lee, J., Bradley, L. M., Dalton, D. K., Christadoss, P., Sarvetnick, N. (1997). Interferon gamma  (IFN-gamma ) Is Necessary for the Genesis of Acetylcholine Receptor-induced Clinical Experimental Autoimmune Myasthenia gravis in Mice. JEM 186: 385-391 [Abstract] [Full Text]  
• Theobald, M., Biggs, J., Hernandez, J., Lustgarten, J., Labadie, C., Sherman, L. A. (1997). Tolerance to p53 by A2.1-restricted Cytotoxic T Lymphocytes. JEM 185: 833-842 [Abstract] [Full Text]  
• von Herrath, M. G., Oldstone, M. B.A. (1997). Interferon-gamma Is Essential for Destruction of beta  Cells and Development of Insulin-dependent Diabetes Mellitus. JEM 185: 531-540 [Abstract] [Full Text]  
• Hudrisier, D., Mazarguil, H., Laval, F., Oldstone, M. B.A., Gairin, J. E. (1996). Binding of Viral Antigens to Major Histocompatibility Complex Class I H-2Db Molecules Is Controlled by Dominant Negative Elements at Peptide Non-anchor Residues. IMPLICATIONS FOR PEPTIDE SELECTION AND PRESENTATION. J. Biol. Chem. 271: 17829-17836 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS