Adaptive NK cells in people exposed to <i>Plasmodium falciparum</i> correlate with protection from malaria

Hart, Geoffrey T.; Tran, Tuan M.; Theorell, Jakob; Schlums, Heinrich; Arora, Gunjan; Rajagopalan, Sumati; Sangala, A. D. Jules; Welsh, Kerry J.; Traoré, Boubacar; Pierce, Susan K.; Crompton, Peter D.; Bryceson, Yenan T.; Long, Eric O.

doi:10.1084/jem.20181681

Cited by 73 publications

(93 citation statements)

References 32 publications

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“…To assess antibody dependent cell cytotoxicity (ADCC), a third well of 5x10 5 PBMC for each sample were mixed with 1.25×10 5 P815 cells (2:1 effector to target (E:T) ratio) pre-incubated with 2.5 g/ml anti-CD32 (Clone 2.4G2, Bio-X-Cell). Cells were incubated in the presence of Golgi Stop and Golgi Plug for a total of 6 hours (Hart et al, 2019). Anti-CD107a (H4A3, Biolegend) at 1:200 dilution was added to all cells in the final 6 hours of stimulation.…”

Section: Methodsmentioning

confidence: 99%

Dynamic changes in natural killer cell subset frequencies in the absence of cytomegalovirus infection

Gyurova

Schlums

Sucharew

et al. 2019

Preprint

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Individuals lacking functional natural killer (NK) cells suffer severe, recurrent infections with cytomegalovirus (CMV), highlighting the critical role of NK cells in antiviral defense. Therefore, ongoing attempts to develop an efficacious vaccine to prevent CMV infection should potentially aim to elicit NK-cell antiviral responses as an accessory to conventional T-and B-cell based approaches. In this regard, CMV infection provokes marked phenotypic and functional differentiation of the NK-cell compartment, including development of adaptive NK cells that exhibit enhanced antiviral activity. We examined longitudinal blood samples collected from 40 CMV-seronegative adolescents to ascertain whether a CMV glycoprotein B (gB) vaccine in the absence of CMV infection can stimulate differentiation or expansion of CMV-associated subsets of NK cells. Study participants uniformly lacked the CMV-dependent NKG2C + subset of NK cells, suggesting that an adjuvanted CMV gB vaccine alone is an inadequate stimulus for sustained expansion of these cells. In contrast, we observed unexpected dynamic fluctuations in the frequency of NK cells lacking FcR, EAT-2, and SYK, which were independent of vaccination or CMV infection. Whereas FcR neg NK cells in CMV infection are reported to express increased levels of the maturation marker CD57, the FcR neg NK cells observed in our CMV-negative vaccine cohort express less CD57 than their FcR + counterparts. The FcR neg NK cells in CMV-negative individuals were also functionally distinct from this subset in CMV infection, exhibiting comparable IFN- production and degranulation as FcR + NK cells in response to cytokine or antibody-dependent stimuli. These results suggest that frequencies of some NK cell subsets may increase in response to unknown environmental or inflammatory cues distinct from that which occurs after CMV infection. Greater understanding of the nature of the signals driving CMVindependent accumulation of these subsets should permit development of mechanisms to facilitate vaccine-driven expansion of CMV-reactive NK cells.Vaccine | HCMV | Innate lymphoid cell | NK cell | Memory | CD56 | CD57 | FcR | SYK | NKG2C | EAT-2

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Section: Methodsmentioning

confidence: 99%

Dynamic changes in natural killer cell subset frequencies in the absence of cytomegalovirus infection

Gyurova

Schlums

Sucharew

et al. 2019

Preprint

Self Cite

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“…Antibodies toward infected erythrocytes can also activate natural killer cells, resulting in degranulation and cytokine production, leading to parasite lysis and growth inhibition . Antibody‐dependent interactions with natural killer cells by infected erythrocytes are dominated by a subset of cells called adaptive natural killer cells . In Mali, people with a higher frequency of these adaptive natural killer cells had lower parasitemia and greater resistance to disease, highlighting the role of natural killer cells in acquired immunity to malaria …”

Section: Functional Antibody In Malariamentioning

confidence: 99%

“…Antibody‐dependent interactions with natural killer cells by infected erythrocytes are dominated by a subset of cells called adaptive natural killer cells . In Mali, people with a higher frequency of these adaptive natural killer cells had lower parasitemia and greater resistance to disease, highlighting the role of natural killer cells in acquired immunity to malaria …”

Section: Functional Antibody In Malariamentioning

confidence: 99%

Antibody effector functions in malaria and other parasitic diseases: a few needles and many haystacks

2020

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Many parasitic infections stimulate antibody responses in their mammalian hosts. The ability of these antibodies to protect against disease varies markedly. Research has revealed that functional properties of antibodies determine their role in protection against parasites. Investigations of antibodies against Plasmodium spp. have demonstrated a variety of functional activities, ranging from invasion inhibition and parasite growth inhibition to antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity. These activities have been demonstrated with a large variety of parasite molecules at multiple life cycle stages, highlighting the importance of functional antibody responses in malaria. Other parasitic infections have not yet been investigated in similar detail, but these mechanisms are likely to operate in nonmalarial parasitic infections as well. In this report, we review data on the role of functional antibody responses in protection from parasitic infections, highlighting discoveries in malaria, a parasite for which our knowledge base is the most advanced.

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“…Adaptive NK cells are involved in immunosurveillance with induction of cytotoxic granules (perforin and granzymes) upon engagement with CD16, NKG2C or activating Killer Immunoglobulin-like Receptor (KIR) (Hwang et al, 2012;Schlums et al, 2015;Tesi et al, 2016). Recently, adaptive CD56 dim NK cells were associated with protection from Plasmodium falciparum (Pf ) malaria (Hart et al, 2019). Pfexposed individual had a higher frequency of FcRγ neg adaptive CD56 dim NK cells and displayed increased antibody-dependent cellular cytotoxicity (ADCC) against Pf-infected red blood cells (Hart et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, adaptive CD56 dim NK cells were associated with protection from Plasmodium falciparum (Pf ) malaria (Hart et al, 2019). Pfexposed individual had a higher frequency of FcRγ neg adaptive CD56 dim NK cells and displayed increased antibody-dependent cellular cytotoxicity (ADCC) against Pf-infected red blood cells (Hart et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

A New Hope for CD56negCD16pos NK Cells as Unconventional Cytotoxic Mediators: An Adaptation to Chronic Diseases

Forconi

Oduor

Oluoch

et al. 2020

Front. Cell. Infect. Microbiol.

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Natural Killer (NK) cells play an essential role in antiviral and anti-tumoral immune responses. In peripheral blood, NK cells are commonly classified into two major subsets: CD56 bright CD16 neg and CD56 dim CD16 pos despite the characterization of a CD56 neg CD16 pos subset 25 years ago. Since then, several studies have described the prevalence of an CD56 neg CD16 pos NK cell subset in viral non-controllers as the basis for their NK cell dysfunction. However, the mechanistic basis for their cytotoxic impairment is unclear. Recently, using a strict flow cytometry gating strategy to exclude monocytes, we reported an accumulation of CD56 neg CD16 pos NK cells in Plasmodium falciparum malaria-exposed children and pediatric cancer patients diagnosed with endemic Burkitt lymphoma (eBL). Here, we use live-sorted cells, histological staining, bulk RNA-sequencing and flow cytometry to confirm that this CD56 neg CD16 pos NK cell subset has the same morphological features as the other NK cell subsets and a similar transcriptional profile compared to CD56 dim CD16 pos NK cells with only 120 genes differentially expressed (fold change of 1.5, p < 0.01 and FDR<0.05) out of 9235 transcripts. CD56 neg CD16 pos NK cells have a distinct profile with significantly higher expression of MPEG1 (perforin 2), FCGR3B (CD16b), FCGR2A, and FCGR2B (CD32A and B) as well as CD6, CD84, HLA-DR, LILRB1/2, and PDCD1 (PD-1), whereas Interleukin 18 (IL18) receptor genes (IL18RAP and IL18R1), cytotoxic genes such as KLRF1 (NKp80) and NCR1 (NKp46), and inhibitory HAVCR2 (TIM-3) are significantly down-regulated compared to CD56 dim CD16 pos NK cells. Together, these data confirm that CD56 neg CD16 pos cells are legitimate NK cells, yet their transcriptional and protein expression profiles suggest their cytotoxic potential is mediated by pathways reliant on antibodies such as antibody-dependent cell cytotoxicity (ADCC), antibody-dependent respiratory burst (ADRB), and enhanced by complement receptor 3 (CR3) and FAS/FASL interaction. Our findings support the premise that chronic diseases induce NK cell Forconi et al. New Hope for CD56 neg CD16 pos NK Cells modifications that circumvent proinflammatory mediators involved in direct cytotoxicity. Therefore, individuals with such altered NK cell profiles may respond differently to NK-mediated immunotherapies, infections or vaccines depending on which cytotoxic mechanisms are being engaged.

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Adaptive NK cells in people exposed to Plasmodium falciparum correlate with protection from malaria

Cited by 73 publications

References 32 publications

Dynamic changes in natural killer cell subset frequencies in the absence of cytomegalovirus infection

Dynamic changes in natural killer cell subset frequencies in the absence of cytomegalovirus infection

Antibody effector functions in malaria and other parasitic diseases: a few needles and many haystacks

A New Hope for CD56negCD16pos NK Cells as Unconventional Cytotoxic Mediators: An Adaptation to Chronic Diseases

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