title: HIV-1-specific cytotoxicity is preferentially mediated by a subset of CD8(+) T cells producing both interferon-gamma and tumor necrosis factor-alpha.
abstract: 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 intraindividual and interindividual differences among epitope-specific T-cell effector functions: while the frequency of HIV-1-specific CD8(+) T cells secreting interferon-gamma but no tumor necrosis factor-alpha (TNF-alpha) following antigenic stimulation was only weakly correlated to their cytotoxic activity (R = 0.05, P =.57), a subset of CD8(+) T cells secreting both inter-feron-gamma and TNF-alpha was substantially more strongly associated with cytotoxicity (R = 0.67, P <.001). 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-gamma 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-gamma and TNF-alpha.
authors.affiliation: Partners AIDS Research Center, Massachusetts General Hospital, 149 13th St, Rm 6613, Boston, MA 02129, USA.
authors.forename: Mathias
authors.initials: M
authors.lastname: Lichterfeld
authors.forename: Xu G
authors.initials: XG
authors.lastname: Yu
authors.forename: Michael T
authors.initials: MT
authors.lastname: Waring
authors.forename: Stanley K
authors.initials: SK
authors.lastname: Mui
authors.forename: Mary N
authors.initials: MN
authors.lastname: Johnston
authors.forename: Daniel
authors.initials: D
authors.lastname: Cohen
authors.forename: Marylyn M
authors.initials: MM
authors.lastname: Addo
authors.forename: John
authors.initials: J
authors.lastname: Zaunders
authors.forename: Galit
authors.initials: G
authors.lastname: Alter
authors.forename: Eunice
authors.initials: E
authors.lastname: Pae
authors.forename: Daryld
authors.initials: D
authors.lastname: Strick
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.forename: Eric S
authors.initials: ES
authors.lastname: Rosenberg
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
mesh_terms: D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000821:virology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D005260:Female; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D013379:Substrate Specificity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases