HIV-1–specific cytotoxicity is preferentially mediated by a subset of CD8+ T cells producing both interferon-γ and tumor necrosis factor–α

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.

Enhanced SIV replication and accelerated progression to AIDS in macaques primed to mount a CD4 T cell response to the SIV envelope protein

“…1C shows a representative result). A more sensitive flow-cytometry CTL assay measuring CTLinduced caspase activation in target cells (12,18) also demonstrated weak or absent SIV-specific CD8 T cell responses (data …”

Influenza Epitope-Specific CD8+ T Cell Avidity, but Not Cytokine Polyfunctionality, Can Be Determined by TCRβ Clonotype

“…Polyfunctional T cells have been associated with delayed disease progression after HIV infection (4)(5)(6)(7), reduced levels of viral replication (6), and the protection afforded either by priming with vaccinia virus or vaccination against Leishmania major (8,9). Greater breadth of cytokine production has also been linked to enhanced cytolytic activity in both HIV-and tumor-specific CD8 + T cells (10)(11)(12). Although there have been several reports linking the functional profiles of T cell populations and their avidity or sensitivity to Ag (6,13,14), these analyses have been largely correlative.…”

Apoptosis of HIV-specific CD8+ T cells: an HIV evasion strategy

“…11 More recently, the preferential ability for cytotoxicity of HIV-specific CD8 þ T cells secreting both IFNg and TNFa was shown. 192 We have previously shown that HIV-and CMV-specific CD8 þ T cells exert similar cytotoxicity. 61 On the other hand, others have described an impaired cytotoxicity for HIV-specific CD8 þ T cells.…”