Characterization of the defective interaction between a subset of natural killer cells and dendritic cells in HIV-1 infection

Mavilio, Domenico; Lombardo, Gabriella; Kinter, Audrey; Fogli, Manuela; Sala, A.; Ortolano, Saida; Farschi, Annahita; Follmann, Dean; Roby, Gregg; Kovacs, Colin; Marcenaro, Emanuela; Pende, Daniela; Moretta, Alessandro; Fauci, Anthony S.

doi:10.1084/jem.20060894

Cited by 166 publications

(175 citation statements)

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“…The perturbations observed in the NK cell compartment during chronic HIV-1 infection include the overall increased activation of NK cells, the early loss of CD3 Ϫ CD56 bright NK cells, the accumulation of anergic CD3 Ϫ CD56 Ϫ CD16 ϩ NK cells (6,10), and the impairment of their cytotoxic capacity (6,9,10,56) and cross-talk with DCs (11). The mechanisms underlying these numeric and functional NK cell perturbations observed during viremic HIV-1 infection are not understood.…”

Section: Discussionmentioning

confidence: 99%

“…NK cells are furthermore capable of secreting a number of cytokines and chemokines early in viral infections that are critical in the initiation of an effective adaptive immune response (5). It has been reported that significant changes occur within the NK cell compartment during HIV-1 infection (6 -9), including perturbations in the distribution and function of NK cells, accumulation of anergic NK cells (6,10), and an impairment of NK-dendritic cell (DC) 3 cross-talk (11). Furthermore, NK cells are activated in HIV-1-infected individuals more than in matched seronegative controls (12).…”

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confidence: 99%

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Single-Stranded RNA Derived from HIV-1 Serves as a Potent Activator of NK Cells

Alter

Suscovich

Teigen

et al. 2007

The Journal of Immunology

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Persistent immune activation is a hallmark of chronic viremic HIV-1 infection. Activation of cells of the innate immune system, such as NK cells, occurs rapidly upon infection, and is sustained throughout the course of the disease. However, the precise underlying mechanism accounting for the persistent HIV-1-induced activation of NK cells is poorly understood. In this study, we assessed the role of uridine-rich ssRNA derived from the HIV-1 long terminal repeat (ssRNA40) on activation of NK cells via TLR7/8. Although dramatic activation of NK cells was observed following stimulation of PBMC with ssRNA40, negligible activation was observed following stimulation of purified NK cells despite their expression of TLR8 mRNA and protein. The functional activation of NK cells by this HIV-1-encoded TLR7/8 ligand could not be reconstituted with exogenous IL-12, IFN-α, or TNF-α, but was critically dependent on the direct contact of NK cells with plasmacytoid dendritic cells or CD14+ monocytes, indicating an important level of NK cell cross-talk and regulation by accessory cells during TLR-mediated activation. Coincubation of monocyte/plasmacytoid dendritic cells, NK cells, and ssRNA40 potentiated NK cell IFN-γ secretion in response to MHC-devoid target cells. Studies using NK cells derived from individuals with chronic HIV-1 infection demonstrated a reduction of NK cell responsiveness following stimulation with TLR ligands in viremic HIV-1 infection. These data demonstrate that HIV-1-derived TLR ligands can contribute to the immune activation of NK cells and may play an important role in HIV-1-associated immunopathogenesis and NK cell dysfunction observed during acute and chronic viremic HIV-1 infection.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Single-Stranded RNA Derived from HIV-1 Serves as a Potent Activator of NK Cells

Alter

Suscovich

Teigen

et al. 2007

The Journal of Immunology

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“…However, a study by Alter et al has shown that even though viremic HIV-1 infection is associated with a reduction in NK cell numbers and a perturbation of NK cell subsets, the overall NK cell activity is increased (46). In addition, a recent report has shown that in HIV-1-infected viremic patients a subset of NK cells lacking the expression of CD56 (CD56 Ϫ NK cells) has an altered expression of NKp30, a NCR, which leads to highly defective NK cell-mediated lysis of autologous dendritic cells (47).…”

mentioning

confidence: 99%

Natural Killer Cells in Perinatally HIV-1-Infected Children Exhibit Less Degranulation Compared to HIV-1-Exposed Uninfected Children and Their Expression of KIR2DL3, NKG2C, and NKp46 Correlates with Disease Severity

Ballan

Long

et al. 2007

The Journal of Immunology

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NK cells play an integral role in the innate immune response by targeting virally infected and transformed cells with direct killing and providing help to adaptive responses through cytokine secretion. Whereas recent studies have focused on NK cells in HIV-1-infected adults, the role of NK cells in perinatally HIV-1-infected children is less studied. Using multiparametric flow cytometric analysis, we assessed the number, phenotype, and function of NK cell subsets in the peripheral blood of perinatally HIV-1-infected children on highly active antiretroviral therapy and compared them to perinatally exposed but uninfected children. We observed an increased frequency of NK cells expressing inhibitory killer Ig-like receptors in infected children. This difference existed despite comparable levels of total NK cells and NK cell subpopulations between the two groups. Additionally, NK cell subsets from infected children expressed, with and without stimulation, significantly lower levels of the degranulation marker CD107, which correlates with NK cell cytotoxicity. Lastly, increased expression of KIR2DL3, NKG2C, and NKp46 on NK cells correlated with decreased CD4+ T-lymphocyte percentage, an indicator of disease severity in HIV-1- infected children. Taken together, these results show that HIV-1-infected children retain a large population of cytotoxically dysfunctional NK cells relative to perinatally exposed uninfected children. This reduced function appears concurrently with distinct NK cell surface receptor expression and is associated with a loss of CD4+ T cells. This finding suggests that NK cells may have an important role in HIV-1 disease pathogenesis in HIV-1-infected children.

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“…In line with these data, NK cells from acute myeloid leukemia (AML) and HIV patients, which frequently express an NKp30 dull phenotype 63,64 had an impaired ability of killing DCs. 65,66 Moreover killing of DCs can also be inhibited in the presence of TGF-b, a cytokine inducing a profound downregulation of the surface expression of NKp30. 67 On the other hand tryptophan, catabolite L-kynurenine (IDO), although affecting NK cell-mediated killing of tumor cells by downregulating the expression of NKp46 and NKG2D, does not impair NK-mediated DC killing because it has no effect on NKp30 expression.…”

mentioning

confidence: 99%