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Blood, 15 July 2004, Vol. 104, No. 2, pp. 487-494.
Prepublished online as a Blood First Edition Paper on April 1, 2004; DOI 10.1182/blood-2003-12-4341.
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Submitted December 22, 2003
Accepted March 24, 2004
HIV-1-specific cytotoxicity is preferentially mediated by a subset of CD8+ T cells producing both interferon- and tumor-necrosis factor-
Mathias Lichterfeld, Xu G Yu, Michael T Waring, Stanley K Mui, Mary Johnston, Daniel Cohen, Marylyn M Addo, John Zaunders, Galit Alter, Eunice Pae, Daryld Strick, Todd M Allen, Eric S Rosenberg, Bruce D Walker, and Marcus Altfeld*
Partners AIDS Research Center, Massachusetts General Hospital, Boston, MA, USA
Partners AIDS Research Center, Massachusetts General Hospital, Boston, MA, USA; Howard Hughes Medical Institute, USA
Fenway Community Health Care Center, Boston, MA, USA
Centre for Immunology, St. Vincent's Hospital, Sydney, NSW, Australia
* Corresponding author; email: maltfeld{at}partners.org.
CD8+ T cells play a crucial role in the control of viral infections by direct elimination of infected cells and secretion of a number of soluble factors. Recent data suggest that HIV-1-specific CD8+ T cell subsets may differ in their ability to exert these effector functions. Here, we directly compared the cytokine secretion patterns and cytotoxic capacity of HIV-1-specific CD8+ T cells, using a flow-cytometric cytotoxicity assay based on caspase-3 activation in dying target cells. These experiments revealed considerable intra-individual and inter-individual differences among epitope-specific T cell effector functions: While the frequency of HIV-1-specific CD8+ T cells secreting interferon-g but no TNF-a following antigenic stimulation was only weakly correlated to their cytotoxic activity (R=0.15, p=0.27), a subset of CD8+ T cells secreting both interferon-g and TNF-a was substantially more strongly associated with cytotoxicity (R=0.68, p<0.0001). This subset of CD8+ T cells also exhibited stronger intracellular perforin expression and more pronounced direct ex-vivo HIV-1-specific cytoxicity than CD8+ T cells secreting solely interferon-g following sorting of these subpopulations according to their cytokine profile. These results suggest that HIV-1-specific cytotoxicity of CD8+ T cells is preferentially mediated by a subset of CD8+ T cells secreting both interferon-g and TNF-a.
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