OBJECTIVE: Autologous HIV-1-infected CD4 primary T cells (aHIVCD4) have been shown to be largely resistant to natural killer (NK)-cell-mediated lysis because of viral strategies of immune evasion. We have previously shown that a preactivation of NK cells with plasmacytoid dendritic cells can significantly augment lysis of aHIVCD4 through a mechanism dependent on interferon-alpha (IFN-α). DESIGN: The goal of the present study is to identify the specific NK-activating receptors involved in NK lysis of aHIVCD4 following IFN-α activation. METHODS: Peripheral blood mononuclear cells (PBMC) were incubated with aHIVCD4 to induce the secretion of endogenous levels of IFN-α and drive NK activation. We then utilized a standard chromium lysis assay to assess the degree of IFN-α-activated lysis of aHIVCD4 in the presence or absence of masking antibodies to a panel of NK-activating receptors and co-receptors. RESULTS: Direct recognition of HIV-1-infected, but not uninfected, autologous CD4 primary T cells by PBMC induced the secretion IFN-α (median 2280 pg/ml, P < 0.001, n = 9) that, in turn, activated NK cells (P < 0.001, n = 12) and significantly increased their cytolytic potential against aHIVCD4 (P < 0.01, n = 12). The masking of NKp46 (P < 0.01, n = 8) and NKG2D (P < 0.05, n = 8), but not 2B4, NTBA, NKp30 or NKp44, significantly reduced IFN-α-activated lysis of aHIVCD4. CONCLUSIONS: Taken together, these results demonstrate that endogenous levels of IFN-α secreted by plasmacytoid dendritic cells induce NK cells to lyse aHIVCD4 via the engagement of NKp46 and NKG2D.
Lysis of HIV-1-infected autologous CD4+ primary T cells by interferon-alpha-activated NK cells requires NKp46 and NKG2D / C. Tomescu, D. Mavilio, L.J. Montaner. - In: AIDS. - ISSN 0269-9370. - 29:14(2015 Sep), pp. 1767-1773. [10.1097/QAD.0000000000000777]
Lysis of HIV-1-infected autologous CD4+ primary T cells by interferon-alpha-activated NK cells requires NKp46 and NKG2D
D. MavilioSecondo
;
2015
Abstract
OBJECTIVE: Autologous HIV-1-infected CD4 primary T cells (aHIVCD4) have been shown to be largely resistant to natural killer (NK)-cell-mediated lysis because of viral strategies of immune evasion. We have previously shown that a preactivation of NK cells with plasmacytoid dendritic cells can significantly augment lysis of aHIVCD4 through a mechanism dependent on interferon-alpha (IFN-α). DESIGN: The goal of the present study is to identify the specific NK-activating receptors involved in NK lysis of aHIVCD4 following IFN-α activation. METHODS: Peripheral blood mononuclear cells (PBMC) were incubated with aHIVCD4 to induce the secretion of endogenous levels of IFN-α and drive NK activation. We then utilized a standard chromium lysis assay to assess the degree of IFN-α-activated lysis of aHIVCD4 in the presence or absence of masking antibodies to a panel of NK-activating receptors and co-receptors. RESULTS: Direct recognition of HIV-1-infected, but not uninfected, autologous CD4 primary T cells by PBMC induced the secretion IFN-α (median 2280 pg/ml, P < 0.001, n = 9) that, in turn, activated NK cells (P < 0.001, n = 12) and significantly increased their cytolytic potential against aHIVCD4 (P < 0.01, n = 12). The masking of NKp46 (P < 0.01, n = 8) and NKG2D (P < 0.05, n = 8), but not 2B4, NTBA, NKp30 or NKp44, significantly reduced IFN-α-activated lysis of aHIVCD4. CONCLUSIONS: Taken together, these results demonstrate that endogenous levels of IFN-α secreted by plasmacytoid dendritic cells induce NK cells to lyse aHIVCD4 via the engagement of NKp46 and NKG2D.File | Dimensione | Formato | |
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