Abstract
CD8+ lymphocytes are believed to be important in host defence against the human immunodeficiency virus (HIV)-1, inhibiting HIV-1 replication through both cytolytic and non-cytolytic pathways1,2,3. The cytolytic pathway involves calcium-dependent exocytosis of perforin and granzyme proteases, as well as Fas-mediated programmed cell death4, whereas the noncytolytic pathway involves the release of chemokines that prevent viral entry5. Using granzyme A as a marker of cytolytic granule proteins, and macrophage inflammatory protein (MIP)-1α and RANTES as markers of HIV-1 inhibitory chemokines, we show that these two very different mediators of viral inhibition are both localized in the cytolytic granules of HIV-1-specific CD8+ cytotoxic T lymphocytes (CTL). Following antigen-specific activation, these mediators are secreted together, facilitating both lysis of virion-producing cells and the inhibition of free virus. In addition, RANTES, MIP-1α and MIP-1β are secreted by CTL as a macromolecular complex containing sulphated proteoglycans. This association appears to have a functional significance, because heparan sulphate facilitates RANTES inhibition of HIV-1 infection of monocytes.
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References
Walker, C. M., Moody, D. J., Stites, D. P. & Levy, J. A. CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science 234, 1563–1566 (1986).
Tsubota, H., Lord, C. I., Watkins, D. I., Morimoto, C. & Letvin, N. L. Acytotoxic T lymphocyte inhibits acquired immunodeficiency syndrome virus replication in peripheral blood lymphocytes. J. Exp. Med. 169, 1421–1434 (1989).
Yang, O. O.et al. Suppression of HIV replication by CD8+ cells: evidence for HLA class I-restricted triggering of cytolytic and non-cytolytic mechanisms. J. Virol. 71, 3120–3128 (1997).
Berke, G. The CTL's kiss of death. Cell 81, 9–12 (1995).
Cocchi, F.et al. Identification of RANTES, MIP-1α, and MIP-1β as the major HIV-suppressive factors produced by CD8+ T cells. Science 270, 1811–1815 (1996).
MacDermott, R. P.et al. Proteoglycans in cell-mediated cytotoxicity. Identification, localization, and exocytosis of a chondroitin sulfate proteoglycan from human cloned natural killer cells during target cell lysis. J. Exp. Med. 162, 1771–1787 (1985).
Stevens, R. S.et al. Co-sedimentation of chondroitin sulfate A glycosaminoglycans and proteoglycans with the cytolytic secretory granules of rat large granular lymphocyte (LGL) tumor cells, and identification of mRNA in normal and transformed LGL that encodes proteoglycans. J. Immunol. 139, 863–868 (1987).
Tschopp, J. & Masson, D. Inhibition of the lytic activity of perforin (cytolysin) and of late complement components by proteoglycans. Mol. Immunol. 24, 907–913 (1987).
Witt, D. P. & Lander, A. D. Differential binding of chemokines to glycosominoglycan subpopulations. Curr. Biol. 4, 394–400 (1994).
Luster, A. D., Greengerg, S. & Leder, P. The IP-10 chemokine binds to a specific cell surface heparan sulfate site shared with platelet factor 4 and inhibits endothelial cell proliferation. J. Exp. Med. 182, 219–231 (1995).
Tanaka, Y.et al. T-cell adhesion induced by proteogican-immobilized cytokine MIP-1β. Nature 361, 79–82 (1993).
Webb, L. M. C., Ehrengruber, M. U., Clark-Lewis, I., Baggiolini, M. & Rot, A. Binding to heparan sulfate or heparin enhances neutrophil responses to interlukin 8. Proc. Natl Acad. Sci. USA 90, 7158–7162 (1993).
Kaplan, K. L., Broekman, M. J., Chernoff, A., Lesznik, G. R. & Drillings, M. Platelet α-granule proteins: Studies on release and subcellular localization. Blood 53, 604–618 (1979).
Levine, S. P., Knieriem, L. K. & Pager, M. A. Platelet factor 4 and the platelet secreted proteoglycan: Immunologic characterization by crossed immunoelectrophesis. Blood 75, 902–910 (1990).
Patel, M.et al. Cell-surface heparan sulfate proteoglycans mediate HIV-1 infection of T-cell lines. AIDS Res. Human Retro. 9, 167–174 (1993).
Moriuchi, H., Moriuchi, M., Combadiere, C., Murphy, P. M. & Fauci, A. S. CD8+ T-cell-derived soluble factor(s), but not β-chemokines RANTES, MIP-1α, and MIP-1β, suppress HIV-1 replication in monocyte/macrophage. Proc. Natl Acad. Sci. USA 93, 15341–15345 (1996).
Dragic, T.et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 381, 667–673 (1996).
Schmidtmayerova, H., Sherry, B. & Bukrinsky, M. Chemokines and HIV replication. Nature 382, 767 (1996).
Simmons, G.et al. Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist. Science 276, 276–279 (1997).
Oravez, T.et al. Regulation of Anti-HIV-1 activity of RANTES by heparan sulfate protoglycans. J. Immunol. 159, 4587–4592 (1997).
Uhlin-Hansen, L., Eskeland, T. & Kolset, S. O. Modulation of the expression of chondroitin sulfate proteoglycan in stimulated human monocytes. J. Biol. Chem. 264, 14916–14922 (1989).
Yeaman, C. & Rapraeger, A. C. Membrane-anchored proteoglycans of mouse macrophages: P388D1 cells express a syndecan-4-like heparan sulfate proteoglycan and a distinct chondroitin sulfate form. J. Cell. Phys. 157, 413–425 (1993).
Alkhatib, G.et al. CC CKR5: a RANTES, MIP-1α, MIP-1β receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 272, 1955–1958 (1996).
Verani, A.et al. C-C chemokines released by lipopolysaccharide (LPS)-stimulated human macrophages suppress HIV-1 infection in both macrophages and T cells. J. Exp. Med. 185, 805–816 (1997).
Walker, B. D.et al. Long-term culture and fine specificity of human cytotoxic T-lymphocyte clones reactive with human immunodeficiency virus type 1. Proc. Natl Acad. Sci. USA 86, 9514–9518 (1989).
Kalams, S. A.et al. Longitudinal analysis of T cell receptor (TCR) gene usage by human immunodeficiency virus 1 enveope-specific cytotoxic T lymphocyte clones reveals a limited TCR repertoire. J. Exp. Med. 179, 1261–1271 (1994).
Pasternack, M. S. & Eisen, N. H. Anovel serine esterase expressed by cytotoxic T lymphocytes. Nature 314, 743–745 (1985).
Pasternack, M. S., Verret, C. R., Liu, M. A. & Eisen, H. N. Serine esterase in cytolytic T lymphocytes. Nature 322, 740–743 (1986).
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We thank R. Stevens and M. Norcross for helpful discussions.
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Wagner, L., Yang, O., Garcia-Zepeda, E. et al. β-Chemokines are released from HIV-1-specific cytolytic T-cell granules complexed to proteoglycans. Nature 391, 908–911 (1998). https://doi.org/10.1038/36129
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DOI: https://doi.org/10.1038/36129
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