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

doi:10.1084/jem.192.1.63

Published online 3 July 2000.

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© The Rockefeller University Press, 0022-1007/2000/7/63/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 1, July 3, 2000 63-76

Original Article

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

Victor Appay^a, Douglas F. Nixon^c, Sean M. Donahoe^c, Geraldine M.A. Gillespie^a, Tao Dong^a, Abigail King^a, Graham S. Ogg^a, Hans M.L. Spiegel^c, Christopher Conlon^b, Celsa A. Spina^d,e, Diane V. Havlir^d, Douglas D. Richman^d,e, Anele Waters^f, Philippa Easterbrook^f, Andrew J. McMichael^a, and Sarah L. Rowland-Jones^a
^a Medical Research Council Human Immunology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom
^b Nuffield Department of Medicine, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
^c Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York 10016
^d University of California at San Diego, La Jolla, California 92093-0679
^e Veterans Administration Research Center for AIDS and HIV Infection, San Diego, California 92063
^f The Caldecot Centre, King's Healthcare National Health Service Trust, London SE5 9RS, United Kingdom

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 leukocyteantigen (HLA) class I tetrameric complexes to identify antigen-specificCD8⁺ T cells has provided a major development in our understandingof their role in controlling viral infections. However, questionsremain about the exact function of these cells, particularlyin HIV infection. Virus-specific cytotoxic T lymphocytes exertmuch of their activity by secreting soluble factors such ascytokines and chemokines. We describe here a method that combinesthe use of tetramers and intracellular staining to examine thefunctional heterogeneity of antigen-specific CD8⁺ T cells exvivo. After stimulation by specific peptide antigen, secretionof interferon (IFN)- ${gamma}$ , tumor necrosis factor (TNF)- ${alpha}$ , macrophageinflammatory protein (MIP)-1ß, and perforin is analyzedby FACS^® within the tetramer-positive population in peripheralblood. Using this method, we have assessed the functional phenotypeof HIV-specific CD8⁺ T cells compared with cytomegalovirus (CMV)-specificCD8⁺ T cells in HIV chronic infection. We show that the majorityof circulating CD8⁺ T cells specific for CMV and HIV antigensare functionally active with regards to the secretion of antiviralcytokines in response to antigen, although a subset of tetramer-stainingcells was identified that secretes IFN- ${gamma}$ and MIP-1ß butnot TNF- ${alpha}$ . However, a striking finding is that HIV-specific CD8⁺T cells express significantly lower levels of perforin thanCMV-specific CD8⁺ T cells. This lack of perforin is linked withpersistent CD27 expression on HIV-specific cells, suggestingimpaired maturation, and specific lysis ex vivo is lower forHIV-specific compared with CMV-specific cells from the samedonor. Thus, HIV-specific CD8⁺ T cells are impaired in cytolyticactivity.

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

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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]
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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]
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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]
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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]
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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]
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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]
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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]
Wherry, E. J., Ahmed, R. (2004). Memory CD8 T-Cell Differentiation during Viral Infection. J. Virol. 78: 5535-5545 [Full Text]
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Fuller, M. J., Khanolkar, A., Tebo, A. E., Zajac, A. J. (2004). Maintenance, Loss, and Resurgence of T Cell Responses During Acute, Protracted, and Chronic Viral Infections. J. Immunol. 172: 4204-4214 [Abstract] [Full Text]
Boon, A. C. M., de Mutsert, G., Fouchier, R. A. M., Sintnicolaas, K., Osterhaus, A. D. M. E., Rimmelzwaan, G. F. (2004). Preferential HLA Usage in the Influenza Virus-Specific CTL Response. J. Immunol. 172: 4435-4443 [Abstract] [Full Text]
Zaunders, J. J., Dyer, W. B., Wang, B., Munier, M. L., Miranda-Saksena, M., Newton, R., Moore, J., Mackay, C. R., Cooper, D. A., Saksena, N. K., Kelleher, A. D. (2004). Identification of circulating antigen-specific CD4+ T lymphocytes with a CCR5+, cytotoxic phenotype in an HIV-1 long-term nonprogressor and in CMV infection. Blood 103: 2238-2247 [Abstract] [Full Text]