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M.F.C. Callan^*, L. Tan^*, N. Annels, G.S. Ogg^*, J.D.K. Wilson^*, C.A. O'Callaghan^*, N. Steven, A.J. McMichael^*, and A.B. Rickinson

From the ^* Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, United Kingdom; and the Cancer Research Campaign Institute for Cancer Studies, University of Birmingham, Birmingham, B15 2TT, United Kingdom

Primary infection with virus can stimulate a vigorous cytotoxic T cell response. The magnitude of the antigen-specific component versus the bystander component of a primary T cell response remains controversial. In this study, we have used tetrameric major histocompatibility complex–peptide complexes to directly visualize antigen-specific cluster of differentration (CD)8⁺ T cells during the primary immune response to Epstein-Barr virus (EBV) infection in humans. We show that massive expansion of activated, antigen-specific T cells occurs during the primary response to this virus. In one individual, T cells specific for a single EBV epitope comprised 44% of the total CD8⁺ T cells within peripheral blood. The majority of the antigen-specific cells had an activated/memory phenotype, with expression of human histocompatibility leukocyte antigen (HLA) DR, CD38, and CD45RO, downregulation of CD62 leukocyte (CD62L), and low levels of expression of CD45RA. After recovery from AIM, the frequency of antigen-specific T cells fell in most donors studied, although populations of antigen-specific cells continued to be easily detectable for at least 3 yr.

Abbreviations used: AIM, acute infectious mononucleosis; CD, cluster of differentiation; EBNA, Epstein-Barr nuclear antigen; IM, infectious mononucleosis.

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• Moosmann, A., Khan, N., Cobbold, M., Zentz, C., Delecluse, H.-J., Hollweck, G., Hislop, A. D., Blake, N. W., Croom-Carter, D., Wollenberg, B., Moss, P. A. H., Zeidler, R., Rickinson, A. B., Hammerschmidt, W. (2002). B cells immortalized by a mini-Epstein-Barr virus encoding a foreign antigen efficiently reactivate specific cytotoxic T cells. Blood 100: 1755-1764 [Abstract] [Full Text]  
• Wu, J., Groh, V., Spies, T. (2002). T Cell Antigen Receptor Engagement and Specificity in the Recognition of Stress-Inducible MHC Class I-Related Chains by Human Epithelial {gamma}{delta} T Cells. J. Immunol. 169: 1236-1240 [Abstract] [Full Text]  
• Dunne, P. J., Faint, J. M., Gudgeon, N. H., Fletcher, J. M., Plunkett, F. J., Soares, M. V. D., Hislop, A. D., Annels, N. E., Rickinson, A. B., Salmon, M., Akbar, A. N. (2002). Epstein-Barr virus-specific CD8+ T cells that re-express CD45RA are apoptosis-resistant memory cells that retain replicative potential. Blood 100: 933-940 [Abstract] [Full Text]  
• Beverley, P C L (2002). Immunology of vaccination. Br Med Bull 62: 15-28 [Abstract] [Full Text]  
• McMichael, A., Mwau, M., Hanke, T. (2002). Design and tests of an HIV vaccine. Br Med Bull 62: 87-98 [Abstract] [Full Text]  
• Uda, H., Mima, T., Yamaguchi, N., Katada, Y., Fukuda, M., Fujii, N., Nakamura, K., Saiki, O. (2002). Expansion of a CD28-Intermediate Subset among CD8 T Cells in Patients with Infectious Mononucleosis. J. Virol. 76: 6602-6608 [Abstract] [Full Text]  
• Wills, M. R., Okecha, G., Weekes, M. P., Gandhi, M. K., Sissons, P. J. G., Carmichael, A. J. (2002). Identification of Naive or Antigen-Experienced Human CD8+ T Cells by Expression of Costimulation and Chemokine Receptors: Analysis of the Human Cytomegalovirus-Specific CD8+ T Cell Response. J. Immunol. 168: 5455-5464 [Abstract] [Full Text]  
• Tomiyama, H., Matsuda, T., Takiguchi, M. (2002). Differentiation of Human CD8+ T Cells from a Memory to Memory/Effector Phenotype. J. Immunol. 168: 5538-5550 [Abstract] [Full Text]  
• Zivna, I., Green, S., Vaughn, D. W., Kalayanarooj, S., Stephens, H. A. F., Chandanayingyong, D., Nisalak, A., Ennis, F. A., Rothman, A. L. (2002). T Cell Responses to an HLA-B*07-Restricted Epitope on the Dengue NS3 Protein Correlate with Disease Severity. J. Immunol. 168: 5959-5965 [Abstract] [Full Text]  
• Wherry, E. J., McElhaugh, M. J., Eisenlohr, L. C. (2002). Generation of CD8+ T Cell Memory in Response to Low, High, and Excessive Levels of Epitope. J. Immunol. 168: 4455-4461 [Abstract] [Full Text]  
• Wilson, A. D., Morgan, A. J. (2002). Primary Immune Responses by Cord Blood CD4+ T Cells and NK Cells Inhibit Epstein-Barr Virus B-Cell Transformation In Vitro. J. Virol. 76: 5071-5081 [Abstract] [Full Text]  
• Catalina, M. D., Sullivan, J. L., Brody, R. M., Luzuriaga, K. (2002). Phenotypic and Functional Heterogeneity of EBV Epitope-Specific CD8+ T Cells. J. Immunol. 168: 4184-4191 [Abstract] [Full Text]  
• Valmori, D., Dutoit, V., Schnuriger, V., Quiquerez, A.-L., Pittet, M. J., Guillaume, P., Rubio-Godoy, V., Walker, P. R., Rimoldi, D., Lienard, D., Cerottini, J.-C., Romero, P., Dietrich, P.-Y. (2002). Vaccination with a Melan-A Peptide Selects an Oligoclonal T Cell Population with Increased Functional Avidity and Tumor Reactivity. J. Immunol. 168: 4231-4240 [Abstract] [Full Text]  
• Grunewald, J, Wahlstrom, J, Berlin, M, Wigzell, H, Eklund, A, Olerup, O (2002). Lung restricted T cell receptor AV2S3+ CD4+ T cell expansions in sarcoidosis patients with a shared HLA-DR{beta} chain conformation. Thorax 57: 348-352 [Abstract] [Full Text]  
• Davenport, M. P., Fazou, C., McMichael, A. J., Callan, M. F. C. (2002). Clonal Selection, Clonal Senescence, and Clonal Succession: The Evolution of the T Cell Response to Infection with a Persistent Virus. J. Immunol. 168: 3309-3317 [Abstract] [Full Text]  
• Appay, V., Papagno, L., Spina, C. A., Hansasuta, P., King, A., Jones, L., Ogg, G. S., Little, S., McMichael, A. J., Richman, D. D., Rowland-Jones, S. L. (2002). Dynamics of T Cell Responses in HIV Infection. J. Immunol. 168: 3660-3666 [Abstract] [Full Text]  
• Sester, M., Sester, U., Gartner, B., Kubuschok, B., Girndt, M., Meyerhans, A., Kohler, H. (2002). Sustained High Frequencies of Specific CD4 T Cells Restricted to a Single Persistent Virus. J. Virol. 76: 3748-3755 [Abstract] [Full Text]  
• Manfras, B. J., Reuter, S., Wendland, T., Kern, P. (2002). Increased Activation and Oligoclonality of Peripheral CD8+ T Cells in the Chronic Human Helminth Infection Alveolar Echinococcosis. Infect. Immun. 70: 1168-1174 [Abstract] [Full Text]  
• Garba, M. L., Pilcher, C. D., Bingham, A. L., Eron, J., Frelinger, J. A. (2002). HIV Antigens Can Induce TGF-{beta}1-Producing Immunoregulatory CD8+ T Cells. J. Immunol. 168: 2247-2254 [Abstract] [Full Text]  
• Koehne, G., Smith, K. M., Ferguson, T. L., Williams, R. Y., Heller, G., Pamer, E. G., Dupont, B., O'Reilly, R. J. (2002). Quantitation, selection, and functional characterization of Epstein-Barr virus-specific and alloreactive T cells detected by intracellular interferon-gamma production and growth of cytotoxic precursors. Blood 99: 1730-1740 [Abstract] [Full Text]  

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