[show abstract][hide abstract] ABSTRACT: NK cells represent a critical component of the host innate immune response to viral infection and tumor transformation. Nevertheless, the fate of recently degranulated NK cells subsequent to a primary target cell interaction remains largely unexplored. Here, we investigated the long-term viability and killing potential of human NK cells following target cell lysis using live-sorting of CD107a-degranulated NK cells. We observed that sorted CD107a+ NK cells exhibited continued lytic potential against a wide variety of target cells, including tumor and virally infected target cells. CD107a-positive- and CD107a-negative-sorted NK cells displayed similar long-term viability, killing potential, and response to inflammatory cytokines such as IL-2, IL-15, and IFN-alpha. Interestingly, we observed that the CD107a signature is remarkably stable over time and that recently degranulated NK cells exhibit an amplification of CD107 expression immediately following a target cell interaction. Together, our data expand previous data showing that NK cells retain the capacity to kill multiple target cells in succession and reveal that NK viability, cytotoxicity, and response to inflammatory cytokines are not altered following a primary target cell interaction. Overall, our data argue for the strength of the NK cell compartment in the continuous surveillance of tumor and virally infected cells in the body and highlight the use of using CD107a expression as a stable marker for NK cytotoxicity.
Journal of leukocyte biology 03/2009; 85(5):871-6. · 4.99 Impact Factor
[show abstract][hide abstract] ABSTRACT: In vivo, several mechanisms have been postulated to protect HIV-1-infected cells from NK surveillance. In vitro, previous research indicates HIV-1-infected autologous CD4(+) primary T cells are resistant to NK lysis. We hypothesized that NK lysis of HIV-1-infected target cells would be augmented by the presence of accessory cells and/or accessory cell factors. In this study, we show that stimulation of plasmacytoid dendritic cells (PDC) with the TLR9 agonist, CpG ODN 2216, triggered NK lysis of HIV-1-infected autologous CD4(+) primary T cells. PDC-stimulated NK lysis was dependent upon MHC class I (MHC-I) down-regulation on infected cells, and primary HIV-1 isolates that exhibited enhanced MHC-I down-regulation were more susceptible to NK-mediated lysis. PDC-stimulated NK lysis of HIV-1-infected autologous CD4(+) primary T cells was blocked by neutralizing Abs to type 1 IFN and was perforin/granzyme dependent. Overall, our data suggest that HIV-infected cells are not innately resistant to NK lysis, and that exogenous NK stimulation derived from PDC can trigger NK cytotoxicity against HIV-1-infected autologous CD4(+) primary T cells.
The Journal of Immunology 09/2007; 179(4):2097-104. · 5.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: The kinetics of recovery for innate immune effectors following antiretroviral therapy are unknown.
Multiple sequential cryopreserved samples (viremic and ART-suppressed) from 66 patients enrolled in the Women's Interagency HIV Study or Multicenter AIDS Cohort Study cohorts (median follow-up, 700 days) were analyzed to determine natural killer, dendritic and T-cell changes by flow cytometry. Functional parameters were also measured in a subset of samples. Changes over time were analyzed by mixed-effect modeling based on a linear spline with a single knot at 270 days.
Following viral suppression, a rapid rise in CD4 and white blood cell counts and a decline in T-cell activation were confirmed. However, natural killer cell subsets increased after 270 days of therapy, with a negative effect by baseline CD4%. CD123+ plasmacytoid but not myeloid dendritic cells showed a trend to increase during the first 270 days with a positive effect of baseline CD4%; plasmacytoid dendritic cell-induced interferon-alpha production significantly increased by end of follow-up.
The kinetics of natural killer and plasmacytoid dendritic cell recovery are markedly different from those of T-cell subsets, indicative of early and delayed benefits of suppressive regimens.
[show abstract][hide abstract] ABSTRACT: The present study assessed antiviral T cell immune responses in 48 human immunodeficiency virus (HIV)-infected children with a stable or decreasing CD4(+) T cell counts and different levels of viral control, in the presence or absence of antiretroviral therapy. Children with full (<40 copies/mL) or partial (<50,000 copies/mL) virus suppression and with a history of stable CD4(+) T cell counts had significantly increased levels of anti-HIV CD4(+) T cell lymphoproliferative responses, lower levels of CD38(+), and higher CD8(+)/CD28(+) T cell percentage, compared with those in treated children with a lack of virus suppression (>50,000 copies/mL). Levels of anti-HIV CD8(+) T cell activity, although higher in treated children with a lack of virus suppression, were not significantly different between the groups. Although levels of anti-HIV CD4(+) and CD8(+) T cell responses were not associated, these levels of responses were associated with the percentage of specific T cell subsets. Overall, a history of stable CD4(+) T cell counts, as a result of therapy that imparted full or partial virus suppression, was associated with increased levels of anti-HIV CD4(+) T helper responses and decreased T cell activation.
The Journal of Infectious Diseases 10/2003; 188(6):873-82. · 5.85 Impact Factor