Original Article

HIV-specific CD8⁺ T Cells Produce Antiviral Cytokines but Are Impaired in Cytolytic Function

Correspondence to: Andrew J. McMichael, MRC Human Immunology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK. Tel:44-1865-222-336 Fax:44-1865-222-502 E-mail:andrew.mcmichael{at}ndm.ox.ac.uk.

The use of peptide–human histocompatibility leukocyte antigen (HLA) class I tetrameric complexes to identify antigen-specific CD8⁺ T cells has provided a major development in our understanding of their role in controlling viral infections. However, questions remain about the exact function of these cells, particularly in HIV infection. Virus-specific cytotoxic T lymphocytes exert much of their activity by secreting soluble factors such as cytokines and chemokines. We describe here a method that combines the use of tetramers and intracellular staining to examine the functional heterogeneity of antigen-specific CD8⁺ T cells ex vivo. After stimulation by specific peptide antigen, secretion of interferon (IFN)-, tumor necrosis factor (TNF)-, macrophage inflammatory protein (MIP)-1ß, and perforin is analyzed by FACS^® within the tetramer-positive population in peripheral blood. Using this method, we have assessed the functional phenotype of HIV-specific CD8⁺ T cells compared with cytomegalovirus (CMV)-specific CD8⁺ T cells in HIV chronic infection. We show that the majority of circulating CD8⁺ T cells specific for CMV and HIV antigens are functionally active with regards to the secretion of antiviral cytokines in response to antigen, although a subset of tetramer-staining cells was identified that secretes IFN- and MIP-1ß but not TNF-. However, a striking finding is that HIV-specific CD8⁺ T cells express significantly lower levels of perforin than CMV-specific CD8⁺ T cells. This lack of perforin is linked with persistent CD27 expression on HIV-specific cells, suggesting impaired maturation, and specific lysis ex vivo is lower for HIV-specific compared with CMV-specific cells from the same donor. Thus, HIV-specific CD8⁺ T cells are impaired in cytolytic activity.

Key Words: cytotoxic T lymphocytes, HIV, cytokines, tetramers, perforin

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• Clay, C. C., Rodrigues, D. S., Harvey, D. J., Leutenegger, C. M., Esser, U. (2005). Distinct Chemokine Triggers and In Vivo Migratory Paths of Fluorescein Dye-Labeled T Lymphocytes in Acutely Simian Immunodeficiency Virus SIVmac251-Infected and Uninfected Macaques. J. Virol. 79: 13759-13768 [Abstract] [Full Text]  
• Fujiwara, M., Takata, H., Oka, S., Tomiyama, H., Takiguchi, M. (2005). Patterns of Cytokine Production in Human Immunodeficiency Virus Type 1 (HIV-1)-Specific Human CD8+ T Cells after Stimulation with HIV-1-Infected CD4+ T Cells. J. Virol. 79: 12536-12543 [Abstract] [Full Text]  
• Curtsinger, J. M., Lins, D. C., Johnson, C. M., Mescher, M. F. (2005). Signal 3 Tolerant CD8 T Cells Degranulate in Response to Antigen but Lack Granzyme B to Mediate Cytolysis. J. Immunol. 175: 4392-4399 [Abstract] [Full Text]  
• Huang, Y., Obholzer, N., Fayad, R., Qiao, L. (2005). Turning On/Off Tumor-Specific CTL Response during Progressive Tumor Growth. J. Immunol. 175: 3110-3116 [Abstract] [Full Text]  
• Zelinskyy, G., Robertson, S. J., Schimmer, S., Messer, R. J., Hasenkrug, K. J., Dittmer, U. (2005). CD8+ T-Cell Dysfunction due to Cytolytic Granule Deficiency in Persistent Friend Retrovirus Infection. J. Virol. 79: 10619-10626 [Abstract] [Full Text]  
• Lazarevic, V., Nolt, D., Flynn, J. L. (2005). Long-Term Control of Mycobacterium tuberculosis Infection Is Mediated by Dynamic Immune Responses. J. Immunol. 175: 1107-1117 [Abstract] [Full Text]  
• Lohman, B. L., Slyker, J. A., Richardson, B. A., Farquhar, C., Mabuka, J. M., Crudder, C., Dong, T., Obimbo, E., Mbori-Ngacha, D., Overbaugh, J., Rowland-Jones, S., John-Stewart, G. (2005). Longitudinal Assessment of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific Gamma Interferon Responses during the First Year of Life in HIV-1-Infected Infants. J. Virol. 79: 8121-8130 [Abstract] [Full Text]  
• Koibuchi, T., Allen, T. M., Lichterfeld, M., Mui, S. K., O'Sullivan, K. M., Trocha, A., Kalams, S. A., Johnson, R. P., Walker, B. D. (2005). Limited Sequence Evolution within Persistently Targeted CD8 Epitopes in Chronic Human Immunodeficiency Virus Type 1 Infection. J. Virol. 79: 8171-8181 [Abstract] [Full Text]  
• Chakraborty, R., Morel, A.-S., Sutton, J. K., Appay, V., Ripley, R. M., Dong, T., Rostron, T., Ogola, S., Palakudy, T., Musoke, R., D'Agostino, A., Ritter, M., Rowland-Jones, S. L. (2005). Correlates of Delayed Disease Progression in HIV-1-Infected Kenyan Children. J. Immunol. 174: 8191-8199 [Abstract] [Full Text]  
• Monceaux, V., Viollet, L., Petit, F., Fang, R. H. T., Cumont, M.-C., Zaunders, J., Hurtrel, B., Estaquier, J. (2005). CD8+ T Cell Dynamics during Primary Simian Immunodeficiency Virus Infection in Macaques: Relationship of Effector Cell Differentiation with the Extent of Viral Replication. J. Immunol. 174: 6898-6908 [Abstract] [Full Text]  
• Peretz, Y., Alter, G., Boisvert, M.-P., Hatzakis, G., Tsoukas, C. M., Bernard, N. F. (2005). Human Immunodeficiency Virus (HIV)-Specific Gamma Interferon Secretion Directed against All Expressed HIV Genes: Relationship to Rate of CD4 Decline. J. Virol. 79: 4908-4917 [Abstract] [Full Text]  
• McElroy, M. D., Elrefaei, M., Jones, N., Ssali, F., Mugyenyi, P., Barugahare, B., Cao, H. (2005). Coinfection with Schistosoma mansoni Is Associated with Decreased HIV-Specific Cytolysis and Increased IL-10 Production. J. Immunol. 174: 5119-5123 [Abstract] [Full Text]  
• Kawano, K., Efferson, C. L., Peoples, G. E., Carter, D., Tsuda, N., Murray, J. L., Ioannides, C. G. (2005). Sensitivity of Undifferentiated, High-TCR Density CD8+ Cells to Methylene Groups Appended to Tumor Antigen Determines Their Differentiation or Death. Cancer Res. 65: 2930-2937 [Abstract] [Full Text]  
• Betts, M. R., Exley, B., Price, D. A., Bansal, A., Camacho, Z. T., Teaberry, V., West, S. M., Ambrozak, D. R., Tomaras, G., Roederer, M., Kilby, J. M., Tartaglia, J., Belshe, R., Gao, F., Douek, D. C., Weinhold, K. J., Koup, R. A., Goepfert, P., Ferrari, G. (2005). Characterization of functional and phenotypic changes in anti-Gag vaccine-induced T cell responses and their role in protection after HIV-1 infection. Proc. Natl. Acad. Sci. USA 102: 4512-4517 [Abstract] [Full Text]  
• Rock, M. T., Yoder, S. M., Wright, P. F., Talbot, T. R., Edwards, K. M., Crowe, J. E. Jr (2005). Differential Regulation of Granzyme and Perforin in Effector and Memory T Cells following Smallpox Immunization. J. Immunol. 174: 3757-3764 [Abstract] [Full Text]  
• Koneru, M., Schaer, D., Monu, N., Ayala, A., Frey, A. B. (2005). Defective Proximal TCR Signaling Inhibits CD8+ Tumor-Infiltrating Lymphocyte Lytic Function. J. Immunol. 174: 1830-1840 [Abstract] [Full Text]  
• Dong, T., Stewart-Jones, G., Chen, N., Easterbrook, P., Xu, X., Papagno, L., Appay, V., Weekes, M., Conlon, C., Spina, C., Little, S., Screaton, G., van der Merwe, A., Richman, D. D., McMichael, A. J., Jones, E. Y., Rowland-Jones, S. L. (2004). HIV-specific Cytotoxic T Cells from Long-Term Survivors Select a Unique T Cell Receptor. JEM 200: 1547-1557 [Abstract] [Full Text]  
• Dale, C. J., De Rose, R., Stratov, I., Chea, S., Montefiori, D. C., Thomson, S., Ramshaw, I. A., Coupar, B. E. H., Boyle, D. B., Law, M., Kent, S. J. (2004). Efficacy of DNA and Fowlpox Virus Priming/Boosting Vaccines for Simian/Human Immunodeficiency Virus. J. Virol. 78: 13819-13828 [Abstract] [Full Text]  
• Ochsenbein, A. F., Riddell, S. R., Brown, M., Corey, L., Baerlocher, G. M., Lansdorp, P. M., Greenberg, P. D. (2004). CD27 Expression Promotes Long-Term Survival of Functional Effector-Memory CD8+ Cytotoxic T Lymphocytes in HIV-infected Patients. JEM 200: 1407-1417 [Abstract] [Full Text]  
• Aandahl, E. M., Quigley, M. F., Moretto, W. J., Moll, M., Gonzalez, V. D., Sonnerborg, A., Lindback, S., Hecht, F. M., Deeks, S. G., Rosenberg, M. G., Nixon, D. F., Sandberg, J. K. (2004). Expansion of CD7low and CD7negative CD8 T-cell effector subsets in HIV-1 infection: correlation with antigenic load and reversion by antiretroviral treatment. Blood 104: 3672-3678 [Abstract] [Full Text]  
• Ueno, T., Tomiyama, H., Fujiwara, M., Oka, S., Takiguchi, M. (2004). Functionally Impaired HIV-Specific CD8 T Cells Show High Affinity TCR-Ligand Interactions. J. Immunol. 173: 5451-5457 [Abstract] [Full Text]  
• Sun, L., Abdelwahab, S. F., Lewis, G. K., Garzino-Demo, A. (2004). Recall antigen activation induces prompt release of CCR5 ligands from PBMC: implication in memory responses and immunization. Int Immunol 16: 1623-1631 [Abstract] [Full Text]  
• Loffredo, J. T., Sidney, J., Wojewoda, C., Dodds, E., Reynolds, M. R., Napoe, G., Mothe, B. R., O'Connor, D. H., Wilson, N. A., Watkins, D. I., Sette, A. (2004). Identification of Seventeen New Simian Immunodeficiency Virus-Derived CD8+ T Cell Epitopes Restricted by the High Frequency Molecule, Mamu-A*02, and Potential Escape from CTL Recognition. J. Immunol. 173: 5064-5076 [Abstract] [Full Text]  
• Monsurro, V., Wang, E., Yamano, Y., Migueles, S. A., Panelli, M. C., Smith, K., Nagorsen, D., Connors, M., Jacobson, S., Marincola, F. M. (2004). Quiescent phenotype of tumor-specific CD8+ T cells following immunization. Blood 104: 1970-1978 [Abstract] [Full Text]  
• Davenport, M. P., Ribeiro, R. M., Perelson, A. S. (2004). Kinetics of Virus-Specific CD8+ T Cells and the Control of Human Immunodeficiency Virus Infection. J. Virol. 78: 10096-10103 [Abstract] [Full Text]  
• Lichterfeld, M., Yu, X. G., Waring, M. T., Mui, S. K., Johnston, M. N., Cohen, D., Addo, M. M., Zaunders, J., Alter, G., Pae, E., Strick, D., Allen, T. M., Rosenberg, E. S., Walker, B. D., Altfeld, M. (2004). HIV-1-specific cytotoxicity is preferentially mediated by a subset of CD8+ T cells producing both interferon-{gamma} and tumor necrosis factor-{alpha}. Blood 104: 487-494 [Abstract] [Full Text]  
• Lun, W.-H., Takeda, A., Nakamura, H., Kano, M., Mori, K., Sata, T., Nagai, Y., Matano, T. (2004). Loss of virus-specific CD4+ T cells with increases in viral loads in the chronic phase after vaccine-based partial control of primary simian immunodeficiency virus replication in macaques. J. Gen. Virol. 85: 1955-1963 [Abstract] [Full Text]  
• Shacklett, B. L., Cox, C. A., Quigley, M. F., Kreis, C., Stollman, N. H., Jacobson, M. A., Andersson, J., Sandberg, J. K., Nixon, D. F. (2004). Abundant Expression of Granzyme A, but Not Perforin, in Granules of CD8+ T Cells in GALT: Implications for Immune Control of HIV-1 Infection. J. Immunol. 173: 641-648 [Abstract] [Full Text]  
• Ho, L.-P., Urban, B. C., Jones, L., Ogg, G. S., McMichael, A. J. (2004). CD4-CD8{alpha}{alpha} Subset of CD1d-Restricted NKT Cells Controls T Cell Expansion. J. Immunol. 172: 7350-7358 [Abstract] [Full Text]  

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