Adaptive Reconfiguration of Natural Killer Cells in HIV-1 Infection

Peppa, Dimitra; Pedroza-Pacheco, Isabela; Pellegrino, Pierre; Williams, Ian; Maini, Mala K.; Borrow, Persephone

doi:10.3389/fimmu.2018.00474

Cited by 61 publications

(74 citation statements)

References 51 publications

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“…We also show that in our cohort of HIV-infected women, TIGIT + NK cells exhibit a more adaptive/mature phenotype (CD57 hi , NKG2C hi , LILRB1 hi , FcRγ lo , Syk lo ) and adaptive NK cells demonstrated higher TIGIT expression in unsupervised clustering via UMAP. This is consistent with the notion that NK cells undergo an adaptive reconfiguration during HIV infection [65]. Notably, Sarhan et al demonstrated that TIGIT was expressed at lower levels in adaptive NK cells from healthy donors [70].…”

Section: Nk Cells Undergo Significant Changes During Chronic Hiv Infesupporting

confidence: 86%

“…TIGIT + NK cells also exhibited increased responses to PMA/ionomycin, cytokine and tumor cells, compared to TIGIT -NK cells (Figures 5d and 5e). [16,64], with expansion of a hypofunctional CD56 -CD16 + NK cell subpopulation [10,11], downregulation of several activating NK cell receptors [12][13][14], and adaptive reconfiguration [65]. Some of these changes are not observed after treatment or in the setting of natural HIV control [66], indicating that diminished NK cell function could contribute to disease pathogenesis.…”

Section: Tigit Expression Is Associated With Increased Nk Cell Responsesmentioning

confidence: 99%

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TIGIT is upregulated by HIV-1 infection and marks a highly functional adaptive and mature subset of natural killer cells

Vendrame

Seiler

Ranganath

et al. 2019

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Objective: Our objective was to investigate the mechanisms that govern natural killer (NK) cell responses to HIV, with a focus on specific receptor-ligand interactions involved in HIV recognition by NK cells. Design and Methods: We first performed a mass cytometry-based screen of NK cell receptor expression patterns in healthy controls and HIV + individuals. We then focused mechanistic studies on the expression and function of T cell immunoreceptor with Ig and ITIM domains (TIGIT). Results: The mass cytometry screen revealed that TIGIT is upregulated on NK cells of untreated HIV + women, but not in antiretroviral-treated women. TIGIT is an inhibitory receptor that is thought to mark exhausted NK cells; however, blocking TIGIT did not improve anti-HIV NK cell responses. In fact, the TIGIT ligands CD112 and CD155 were not upregulated on CD4 + T cells in vitro or in vivo, providing an explanation for the lack of benefit from TIGIT blockade. TIGIT expression marked a unique subset of NK cells that express significantly higher levels of NK cell activating receptors (DNAM-1, NTB-A, 2B4, CD2) and exhibit a mature/adaptive phenotype (CD57 hi , NKG2C hi , LILRB1 hi , FcRγ lo , Syk lo ). Furthermore, TIGIT + NK cells had increased responses to mock-infected and HIV-infected autologous CD4 + T cells, and to PMA/ionomycin, cytokine stimulation and the K562 cancer cell line. Conclusions: TIGIT expression is increased on NK cells from untreated HIV + individuals. Although TIGIT does not participate directly in NK cell recognition of HIV, it marks a population of mature/adaptive NK cells with increased functional responses. Antibody conjugation, mass cytometry staining and data acquisitionAntibodies were conjugated using MaxPar® ×8 labeling kits (Fluidigm). To ensure antibody stability over time, antibody panels were lyophilized into single-use pellets prior to use (Biolyph). Cells were stained for mass cytometry as described previously [51,52] and resuspended in 1× EQ Beads (Fluidigm) before acquisition on a Helios mass cytometer (Fluidigm). In vitro HIV infectionReplication competent (Q23-FL) HIV-1 was made by transfection and titrated as described [51]. CD4 + T cells were activated for 2 days with plate-bound anti-CD3 (clone OKT3, eBioscience, 10 µg/ml), soluble anti-CD28/CD49d (clones L293/L25, BD Biosciences, 1 µg/ml each) and phytohemagglutinin (eBioscience, 2.5 µg/ml). CD4 + T cells were infected overnight with Q23-FL via ViroMag R/L magnetofection (Oz Biosciences) at a multiplicity of infection of 20. HIV infection was as measured by intracellular p24. TIGIT blockade assayCells were cultured in RPMI media containing 10% FBS (Thermo Fisher Scientific) and 1% penicillin/streptomycin/amphotericin (Thermo Fisher Scientific) (RP10). NK cells were incubated in 24-well plates at a concentration of 2x10 6 cells/ml in for 3 days at 37°C with 5% CO2, with addition of rhIL-2 (R&D Systems, 300 IU/ml). After 3 days, NK cells were washed with fresh media and plated in 96-well plates (80,000-100,000 cells/well). Blocking mIgG1κ anti-h...

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Section: Nk Cells Undergo Significant Changes During Chronic Hiv Infesupporting

confidence: 86%

Section: Tigit Expression Is Associated With Increased Nk Cell Responsesmentioning

confidence: 99%

TIGIT is upregulated by HIV-1 infection and marks a highly functional adaptive and mature subset of natural killer cells

Vendrame

Seiler

Ranganath

et al. 2019

Preprint

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“…PD-1 expression is also increased in HIV infection even with ART treatment, and these cells have limited proliferative capacity and may contribute to NK cell dysfunction (Norris et al, 2012). The increased expression of NKG2C and CD2 may reflect an increase in a subset of NK cells with a more mature, adaptive phenotype that is known to expand during HIV infection, and that persists even during ART treatment (Peppa et al, 2018). Indeed, we observed differential abundance of cluster 3 (Fig 4) between the HIV+ and HIV-groups; this cluster, which had greater abundance in donors of the HIV+ group, expressed high levels of CD2 and low levels of Siglec-7, and expressed both NKG2C and CD57, all known features of this subset.…”

Section: Discussionmentioning

confidence: 99%

Treated HIV Infection Alters Phenotype But Not HIV-specific Function of Peripheral Blood Natural Killer Cells

Zhao

Ferreira

Grant

et al. 2020

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ABSTRACTNatural killer (NK) cells are the predominant antiviral cells of the innate immune system, and may play an important role in acquisition and disease progression of HIV. While untreated HIV infection is associated with distinct alterations in the peripheral blood NK cell repertoire, less is known about how NK phenotype is altered in the setting of long-term viral suppression with antiretroviral therapy (ART), as well as how NK memory can impact functional responses. As such, we sought to identify changes in NK cell phenotype and function using high-dimensional mass cytometry to simultaneously analyze both surface and functional marker expression of peripheral blood NK cells in a cohort of ART-suppressed, HIV+ patients and HIV-healthy controls. We found that the NK cell repertoire following IL-2 treatment was altered in individuals with treated HIV infection compared to healthy controls, with increased expression of markers including NKG2C and CD2, and decreased expression of CD244 and NKp30. Using co-culture assays with autologous, in vitro HIV-infected CD4 T cells, we identified a subset of NK cells with enhanced responsiveness to HIV-1-infected cells, but no differences in the magnitude of anti-HIV NK cell responses between the HIV+ and HIV-groups. In addition, by profiling of NK cell receptors on responding cells, we found similar phenotypes of HIV-responsive NK cell subsets in both groups. Lastly, we identified clusters of NK cells that are altered in individuals with treated HIV infection compared to healthy controls, but found that these clusters are distinct from those that respond to HIV in vitro. As such, we conclude that while chronic, treated HIV infection induces a reshaping of the IL-2-stimulated peripheral blood NK cell repertoire, it does so in a way that does not make the repertoire more HIV-specific.

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“…Natural Killer (NK) cells play a key role in antiviral immunity and a number of studies implicate NK cells as critical contributors to immune control of HIV-1 (Fauci et al, 2005) (Martin et al, 2002) (Martin et al, 2007). It is well documented that persistent HIV-1 infection alters the subset distribution and functional capacity of NK cells (Peppa et al, 2018) (Bradley et al, 2018) (Altfeld et al, 2011). In particular HCMV co-infection, a hallmark of HIV-1 infected cohorts, triggers a dramatic expansion of differentiated NK cells expressing the activating receptor NKG2C, which prototypically characterises adaptive NK cells (Guma et al, 2006) (Mela and Goodier, 2007) (Brunetta et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Notably they resemble memory CD8 T cells and are imbued with enhanced capacity for antibody dependent cellular cytotoxicity (ADCC), in particular increased IFN-γ production attributed to epigenetic remodelling of the IFNG locus (Schlums et al, 2015) (Lee et al, 2015). The adaptive reconfiguration of NK cells during HIV-1 infection is further delineated by loss of the transcription factor promyelocytic leukaemia zinc finger protein (PLZF), and downstream signalling molecules such as FcεRI-γ (Peppa et al, 2018), which partly overlap with NKG2C expression. While these attributes are considered important in the functional specialisation of these NK cells, the development of these features under conditions of continuous stimulation/persistent inflammation during HIV-1 infection could lead to the establishment of functionally and metabolically exhausted NK cells akin to exhausted CD8 T cells.…”

Section: Introductionmentioning

confidence: 99%

IL-15 re-programming compensates for NK cell mitochondrial dysfunction in HIV-1 infection

Cubero

Balint

Alrubayyi³

et al. 2019

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16Dynamic regulation of cellular metabolism is important for maintaining homeostasis and can directly 17 influence immune cell function and differentiation including Natural Killer (NK) cell responses. 18Persistent HIV-1 infection leads to a state of chronic activation, subset redistribution and progressive 45 et al., 2015) (Lee et al., 2015). The adaptive reconfiguration of NK cells during HIV-1 infection is further 46 delineated by loss of the transcription factor promyelocytic leukaemia zinc finger protein (PLZF), and 47 downstream signalling molecules such as FcεRI-γ (Peppa et al., 2018), which partly overlap with 48 NKG2C expression. While these attributes are considered important in the functional specialisation of 49 2 these NK cells, the development of these features under conditions of continuous 50 stimulation/persistent inflammation during HIV-1 infection could lead to the establishment of 51 functionally and metabolically exhausted NK cells akin to exhausted CD8 T cells. In keeping with this 52 notion, chronic stimulation of adaptive NK cells through NKG2C ligation was recently found to lead to 53 a molecular programme of exhaustion that is shared between NK cells and CD8 T cells (Merino et al., 54 2019). Exhausted CD8 T cells are characterised by a number of metabolic defects, however, to date it 55 remains unexplored how persistent HIV-1 infection contributes to the metabolic remodelling of NK 56 cell subsets. NK cell exhaustion could influence responses to CD16 engagement linked to vaccine-57 induced protective immunity against HIV-1 infection and phenotypes of viral control (Scully and Alter, 58 2016). Such knowledge represents a critical first step in our understanding of the metabolic machinery 59 of NK cell subsets with distinct immunologic features that can be potentially targeted for developing 60 new or complementary antiviral approaches aimed at enhancing ADCC responses. 61 62 Whereas metabolic regulation of T cell function is well characterised, evidence of the importance of 63 immunometabolism in facilitating robust NK cell functions is gradually emerging. Notably, impaired 64 NK cell cellular metabolism has been implicated in obesity and cancer, providing a new framework for 65 understanding NK cell functionality (Michelet et al., 2018) (Cong et al., 2018). Studies from both 66 human and murine models have demonstrated that NK cells activated through cytokine stimulation 67 exhibit substantial increases in the rates of both glycolysis and oxidative phosphorylation (OXPHOS) 68 pathways (Marcais et al., 2014) (Donnelly et al., 2014) (Keating et al., 2016; O'Brien and Finlay, 2019). 69However, the metabolic requirement of NK cells for optimal effector function, in terms of IFN- 70 production, depends on the specific activation stimuli. In particular, receptor mediated activation 71 through anti-NK1.1 and anti-Ly49D in mice appears to require OXPHOS as an essential second signal 72 for IFN- production and appears more susceptible to metabolic inhibition compared to cytokine 73 stimulation ...

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Adaptive Reconfiguration of Natural Killer Cells in HIV-1 Infection

Cited by 61 publications

References 51 publications

TIGIT is upregulated by HIV-1 infection and marks a highly functional adaptive and mature subset of natural killer cells

TIGIT is upregulated by HIV-1 infection and marks a highly functional adaptive and mature subset of natural killer cells

Treated HIV Infection Alters Phenotype But Not HIV-specific Function of Peripheral Blood Natural Killer Cells

IL-15 re-programming compensates for NK cell mitochondrial dysfunction in HIV-1 infection

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