Characterization of CD56<sup>–</sup>/CD16<sup>+</sup>natural killer (NK) cells: A highly dysfunctional NK subset expanded in HIV-infected viremic individuals

Mavilio, Domenico; Lombardo, Gabriella; Benjamin, Janet; Kim, Diana; Follman, Dean; Marcenaro, Emanuela; O’Shea, Marie A.; Kinter, Audrey; Kovacs, Colin; Moretta, Alessandro; Fauci, Anthony S.

doi:10.1073/pnas.0409872102

Cited by 487 publications

(560 citation statements)

References 44 publications

(63 reference statements)

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“…These conclusions are supported by the finding of hypofunctional NK cells in UCB that become CD56 + /CD16 + after stimulation with IL-15 [35]. In human disease, HIV infection also seems to uniquely expand a population of dysfunctional CD56 − /CD16 + NK cells in vivo [36]. The receptor repertoire of NK cells found in HIV infected viremic individuals is similar to what we describe here.…”

Section: Discussionsupporting

confidence: 88%

Mouse fetal and embryonic liver cells differentiate human umbilical cord blood progenitors into CD56-negative natural killer cell precursors in the absence of interleukin-15

McCullar

Oostendorp

Panoskaltsis‐Mortari

et al. 2008

Experimental Hematology

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Objective-Human NK cell maturation involves the orderly acquisition of NK cell receptors. Our aim was to understand how stromal interactions and cytokines are important in this developmental process.Methods-Human UCB CD34 + /Lin − /CD38 − cells were cultured on two murine stromal cell lines (AFT024 and EL08-1D2) in a switch culture to study NK cell development.Results-When human progenitors were cultured on AFT024 with IL-3 and Flt3-L in the absence of IL-15, NK cell differentiation occurred, albeit at low frequency. These conditions favored the accumulation of CD56 − NK cell precursors (CD34 + CD7 − , CD34 + CD7 + and CD34 − CD7 + cells), which are populations rare in adult blood but abundant in fresh UCB. In secondary culture, addition of IL-3 or IL-3+Flt3L to IL-15 increased the absolute number of CD56 + NK cells from precursors and the acquisition of CD94 and KIR. To further explore the microenvironment in early NK cell maturation, a cell line derived from murine embryonic liver (EL08-1D2) was studied. NK cell development and KIR acquisition was superior with EL08-1D2 which supported the differentiation of NK cell precursors, NK cell commitment, and proliferation.Conclusion-Although the earliest events in NK cell maturation do not require exogenous human IL-15, it is required at a later stage of NK cell commitment. At a minimum, murine stroma, IL-3, and Flt3-L are required to recapitulate early NK cell development and differentiation into distinct NK cell precursors. EL08-1D2 induces KIR acquisition suggesting that extrinsic signals in NK cell development are conserved between mouse and man.

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Section: Discussionsupporting

confidence: 88%

Mouse fetal and embryonic liver cells differentiate human umbilical cord blood progenitors into CD56-negative natural killer cell precursors in the absence of interleukin-15

McCullar

Oostendorp

Panoskaltsis‐Mortari

et al. 2008

Experimental Hematology

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“…Chronic viremic HIV-1 infection is characterized by persistent immune activation (30) and the functional impairment of several lymphocyte populations (50 -52), including NK cells (9,10,12,(53)(54)(55). 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).…”

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).…”

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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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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“…Peripheral blood mononuclear cells from PWHA with and without KS and from healthy control individuals were analyzed for C-type lectin receptor expression after gating on CD3 Ϫ CD14 Ϫ CD19 Ϫ CD94 ϩ cells as described previously (20). This method defines all of the NKG2A and NKG2C ϩ NK cells in the peripheral blood, including those present within the CD56 Ϫ NK cell population, which is increased in HIV-1 infection (18). The proportion of NKG2C-positive cells was significantly higher in both KS-negative and KS-positive PWHA (median, 50.3 and 46.5%, respectively; range, 0.1 to 96.1% and 1.9 to 85.4%, respectively) than that in healthy controls (median, 12.1%; range, 6.3 to 21%) (Fig.…”

mentioning

confidence: 99%

NKG2C ⁺ NK Cells Are Enriched in AIDS Patients with Advanced-Stage Kaposi's Sarcoma

Goodier

Mela

Steel³

et al. 2007

J Virol

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Kaposi's sarcoma (KS) is an AIDS-defining condition in individuals withRecognition of infected target cells by NK cells is regulated by receptors for major histocompatibility complex class I (MHC-I) and pathogen-derived molecules (3,14). Killer cell immunoglobulin-like receptor (KIR) family members, which are expressed on NK cells, influence the risk of progression to AIDS in combination with HLA-B alleles (15, 16). However, the proportion of NK cells expressing inhibitory KIR increases and those expressing activating natural cytotoxicity receptors (NCR) are less abundant in PWHA (1,5,6,17).We have shown that NK cells from PWHA are enriched for a subset bearing the C-type, lectin-like receptor NKG2C (20). The NKG2C receptor mediates NK cell responses to a limited set of ligands in association with HLA-E, including a human cytomegalovirus (HCMV) peptide, and to HCMV-infected fibroblasts (9, 10). However, NK cells bearing NKG2C predominantly express inhibitory KIR and have low levels of activating NCR, which may compromise their abilities to mount cytolytic responses (8,20).As NKG2C ϩ NK cells have a predominantly inhibitory phenotype, the dominance of this subset could have an impact on disease prognosis in AIDS patients, including those with KS. We used the AIDS Clinical Trial Group (ACTG) clinical staging system, which is applied to all AIDS KS patients upon diagnosis, to investigate the relationship between the NK cell phenotype and function and disease prognosis in HIV-1 infection.Patients

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Characterization of CD56^–/CD16⁺natural killer (NK) cells: A highly dysfunctional NK subset expanded in HIV-infected viremic individuals

Cited by 487 publications

References 44 publications

Mouse fetal and embryonic liver cells differentiate human umbilical cord blood progenitors into CD56-negative natural killer cell precursors in the absence of interleukin-15

Mouse fetal and embryonic liver cells differentiate human umbilical cord blood progenitors into CD56-negative natural killer cell precursors in the absence of interleukin-15

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

NKG2C ⁺ NK Cells Are Enriched in AIDS Patients with Advanced-Stage Kaposi's Sarcoma

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Characterization of CD56–/CD16+natural killer (NK) cells: A highly dysfunctional NK subset expanded in HIV-infected viremic individuals

Cited by 487 publications

References 44 publications

Mouse fetal and embryonic liver cells differentiate human umbilical cord blood progenitors into CD56-negative natural killer cell precursors in the absence of interleukin-15

Mouse fetal and embryonic liver cells differentiate human umbilical cord blood progenitors into CD56-negative natural killer cell precursors in the absence of interleukin-15

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

NKG2C + NK Cells Are Enriched in AIDS Patients with Advanced-Stage Kaposi's Sarcoma

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Characterization of CD56^–/CD16⁺natural killer (NK) cells: A highly dysfunctional NK subset expanded in HIV-infected viremic individuals

NKG2C ⁺ NK Cells Are Enriched in AIDS Patients with Advanced-Stage Kaposi's Sarcoma