Abstract
Understanding the lineage differentiation of memory T cells is a central question in immunology. We investigated this issue by analysing the expression of the chemokine receptor CCR7, which defines distinct subsets of naive and memory T lymphocytes with different homing and effector capacities1,2,3 and antiviral immune responses to HIV and cytomegalovirus. Ex vivo analysis of the expression of CD45RA and CCR7 antigens, together with in vitro analysis of the cell-division capacity of different memory CD8+ T-cell populations, identified four subsets of HIV- and CMV-specific CD8+ T lymphocytes, and indicated the following lineage differentiation pattern: CD45RA+CCR7+ → CD45RA-CCR7+ → CD45RACD45RA-CCR7- → CD45RA+CCR7-. Here we demonstrate through analysis of cell division (predominantly restricted to the CCR7+CD8+ T-cell subsets) that the differentiation of antigen-specific CD8+ T cells is a two-step process characterized initially by a phase of proliferation largely restricted to the CCR7+CD8+ cell subsets, followed by a phase of functional maturation encompassing the CCR7-CD8+ cell subsets. The distribution of these populations in HIV- and CMV-specific CD8+ T cells showed that the HIV-specific cell pool was predominantly (70%) composed of pre-terminally differentiated CD45RA-CCR7- cells, whereas the CMV-specific cell pool consisted mainly (50%) of the terminally differentiated CD45RA+CCR7- cells. These results demonstrate a skewed maturation of HIV-specific memory CD8+ T cells during HIV infection.
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References
Butcher, E. C. & Picker, L. J. Lymphocyte homing and homeostasis. Science 272, 60–66 (1996).
Sallusto, F. et al. The role of chemokine receptors in primary, effector, and memory immune responses. Annu. Rev. Immunol. 18, 593–620 (2000).
Sallusto, F. et al. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).
Pantaleo, G. et al. Major expansion of CD8+ T cells with a predominant V beta usage during the primary immune response to HIV. Nature 370, 463–467 (1994).
Schmitz, J. E. et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283, 857–860 (1999).
Appay, V. et al. HIV-specific CD8+ T cells produce antiviral cytokines but are impaired in cytolytic function. J. Exp. Med. 192, 63–75 (2000).
Altman, J. D. et al. Phenotypic analysis of antigen-specific T lymphocytes. Science 274, 94–96 (1996).
Ogg, G. S. et al. Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science 279, 2103–2106 (1998).
Johnson, R. P. et al. HIV-1 gag-specific cytotoxic T lymphocytes recognize multiple highly conserved epitopes. J. Immunol. 147, 1512–1521 (1991).
Michie, C. A. et al. Lifespan of human lymphocyte subsets defined by CD45 isoforms. Nature 360, 264–265 (1992).
Callan, M. F. C. et al. Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr Virus in vivo. J. Exp. Med. 187, 1395–1402 (1998).
Hamann, D. et al. Phenotypic and functional separation of memory and effector human CD8+ T cells. J. Exp. Med. 186, 1407–1418 (1997).
Lyons, A. B. & Parish, C. R. Determination of lymphocyte division by flow cytometry. J. Immunol. Methods 171, 131–137 (1994).
Gerdes, J. et al. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J. Immunol. 133, 1710–1715 (1984).
Pantaleo, G. et al. Defective clonogenic potential of CD8+ T lymphocytes in patients with AIDS. Expansion in vivo of a nonclonogenic CD3+CD8+DR+CD25- T cell population. J. Immunol. 144, 1696–1704 (1990).
Pantaleo, G. et al. CD8+ T lymphocytes of patients with AIDS maintain normal broad cytolytic function despite the loss of human immunodeficiency virus-specific cytotoxicity. Proc. Natl Acad. Sci. USA 87, 4818–4822 (1990).
Sallusto, F. et al. Switch in chemokine receptor expression upon TCR stimulation reveals novel homing potential for recently activated T cells. Eur. J. Immunol. 29, 2037–2045 (1999).
Wills, M. R. et al. The human cytotoxic T-lymphocyte (CTL) response to Cytomegalovirus is dominated by structural protein pp65: Frequency, specificity, and T-cell receptor usage of pp65-specific CTL. J. Virol. 70, 7569–7579 (1996).
Fleury, S. et al. Limited CD4+ T-cell renewal in early HIV-1 infection: effect of highly active antiretroviral therapy. Nature Medicine 4, 794–801 (1998).
Fleury, S. et al. Long-term kinetics of T cell production in HIV-infected subjects treated with highly active antiretroviral therapy. Proc. Natl Acad. Sci. USA 97, 5393–5398 (2000).
Andersson, J. et al. Perforin is not co-expressed with Granzyme A within cytoxic granules in CD8 T lymphocytes present in lymphoid tissue during chronic HIV infection. AIDS 13, 1295–1303 (1998).
Wolthers, K. C. et al. T cell telomere length in HIV-1 infection: no evidence for increased CD4+ T cell turnover. Science 274, 1543–1547 (1996).
Mitchison, N. A. et al. Proc. R. Soc. Lond. 161, 275–293 (1964).
Zinkernagel, R. M. Immunology taught by viruses. Science 271, 173–178 (1996).
Rosenberg, E. S. et al. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 278, 1447–1450 (1997).
Miedema, F. et al. Changing virus-host interactions in the course of HIV-1 infection. Immunol. Rev. 140, 35–72 (1994).
Acknowledgements
We thank A. Wilson for providing the Extravidin-Cy5 conjugate. This work was supported by an SNF grant (Tandem project), by the EuroVae project (G.P.) and by the Leenards Foundation (G.P.), and by an NIH grant (Acute Infection, G.P.; R.P.S.). P.C. is supported by a Doctoral Award of the Medical Research Council of Canada. R.P.S. is a Canadian Institutes of Health Research senior scientist.
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Champagne, P., Ogg, G., King, A. et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 410, 106–111 (2001). https://doi.org/10.1038/35065118
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DOI: https://doi.org/10.1038/35065118
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