Poorly cytotoxic terminally differentiated CD56negCD16pos NK cells accumulate in Kenyan children with Burkitt lymphomas

Forconi, Catherine S.; Cosgrove, Cormac; Lakshmi, Priya Saikumar; Nixon, Christina E.; Foley, Joslyn; Ong’echa, John Michael; Otieno, Juliana A.; Alter, Galit; Münz, Christian; Moormann, Ann M.

doi:10.1182/bloodadvances.2017015404

Cited by 44 publications

(63 citation statements)

References 66 publications

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“…Finally, the percentage of each NK subset was assessed within the total NK cell population. Consistent with our previous study (Forconi et al, 2018), eBL children had elevated CD56 neg CD16 pos NK cell subset, with a median of 30.3%.…”

Section: Characterization Of the Samplessupporting

confidence: 91%

“…Therefore, baseline peripheral blood samples were used from 8 male eBL children before induction of chemotherapy. However, we have previously shown that both male and female eBL patients have significantly elevated frequencies of CD56 neg CD16 pos NK cells (Forconi et al, 2018).…”

Section: Study Population and Ethical Approvalsmentioning

confidence: 83%

“…To measure IgG antibody levels in the plasma fraction, we used a Luminex bead-based suspension assay as previously published (Cham et al, 2009;Forconi et al, 2018). In brief, antibodies to Viral Capsid Antigen (VCA) and Epstein-Barr nuclear antigen 1 (EBNA1) (gift from Jaap Middeldorp, Cyto-Barr) were used to determine EBV seropositivity (Middeldorp and Herbrink, 1988;van Grunsven et al, 1994).…”

Section: Multiplex Suspension Bead-based Serology Assaymentioning

confidence: 99%

“…Compared to CD56 pos NK cells, CD56 neg NK cells have been portrayed as "dysfunctional" because of lower expression of cytotoxic receptors such as NKp46 and NKp30, low cytokine production as well as reduction of natural cytotoxicity (Mavilio et al, 2005;Müller-Durovic et al, 2019). More recently, we reported a dramatic expansion of CD56 neg CD16 pos NK cells in African children chronically/repeatedly infected with Plasmodium falciparum malaria and in those who were diagnosed with endemic Burkitt lymphoma (eBL) (Forconi et al, 2018). Proteomic analyses showed similarities between CD56 dim CD16 pos and CD56 neg CD16 pos NK cells (Voigt et al, 2018) thus supporting the classification of this subset as NK cells.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Characterization Of the Samplessupporting

confidence: 91%

Section: Study Population and Ethical Approvalsmentioning

confidence: 83%

Section: Multiplex Suspension Bead-based Serology Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…While chronic infections have a profound influence on immune recall responses, whether or not NK memory mechanisms are induced and contribute to antimalarial immunity remains to be determined. The second finding is a recently published longitudinal study of children residing in a malaria holoendemic area that reveals an expansion of licensed CD56 neg CD16 pos NK cells, which has been described for other chronic human infections . The CD56 neg CD16 pos NK cells associated with a history of previous P. falciparum infections had poor direct cytotoxicity, lower expression of NK activation markers (NKp46, NKp30 and CD160) and IFNγ, yet expressed higher levels of MIP1β and CD16.…”

Section: Natural Killer Cellsmentioning

confidence: 56%

Immune effector mechanisms in malaria: An update focusing on human immunity

Moormann

Nixon

Forconi

2019

Parasite Immunology

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The past decade has witnessed dramatic decreases in malaria‐associated mortality and morbidity around the world. This progress has largely been due to intensified malaria control measures, implementation of rapid diagnostics and establishing a network to anticipate and mitigate antimalarial drug resistance. However, the ultimate tool for malaria prevention is the development and implementation of an effective vaccine. To date, malaria vaccine efforts have focused on determining which of the thousands of antigens expressed by Plasmodium falciparum are instrumental targets of protective immunity. The antigenic variation and antigenic polymorphisms arising in parasite genes under immune selection present a daunting challenge for target antigen selection and prioritization, and is a given caveat when interpreting immune recall responses or results from monovalent vaccine trials. Other immune evasion strategies executed by the parasite highlight the myriad of ways in which it can become a recurrent infection. This review provides an update on immune effector mechanisms in malaria and focuses on our improved ability to interrogate the complexity of human immune system, accelerated by recent methodological advances. Appreciating how the human immune landscape influences the effectiveness and longevity of antimalarial immunity will help explain which conditions are necessary for immune effector mechanisms to prevail.

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Differential expression of maturation and activation markers on NK cells in patients with active and latent tuberculosis

Albayrak

Dirix

Aerts

et al. 2021

Journal of Leukocyte Biology

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NK cells were recently suggested to be important for the initial control of M. tuberculosis infection. The phenotypes of the 3 main NK blood subsets, CD56bright, CD56dim, and CD56neg cells, were characterized by flow cytometry in a cohort of 81 prospectively enrolled subjects (21 untreated patients with active tuberculosis ‐aTB‐, 35 latently TB infected ‐LTBI‐ subjects, and 25 non‐infected controls), using 9 different mAbs added to whole blood. Compared to LTBI subjects, patients with aTB had lower proportions of total NK cells, lower proportions and numbers of CD56neg cells expressing early maturation markers (CD161, NKp30, NKp46), but higher density of NKp30 and NKp46 expression on both CD56neg and CD56dim subsets, associated with higher expression of granzymes A/B. They also had higher proportions of activated CD69pos cells within all 3 NK cell subsets and, the percentage of CD69pos CD56dim cells among CD69pos and/or NKG2Cpos NK cells was identified as a potential biomarker to discriminate aTB from LTBI. LTBI subjects were in contrast characterized by higher expression of late maturation markers (CD57, KIR molecules) on the CD56neg subset, by higher proportions of NKG2CposKIRpos CD56dim NK cells, and by higher in vitro IFN‐γ production than patients with aTB. Thus, the in‐depth phenotypic characterization of blood NK cell subsets provides new insights on possible functional modifications and the potential role of NK cells in the control of M. tuberculosis infection in humans.

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Poorly cytotoxic terminally differentiated CD56negCD16pos NK cells accumulate in Kenyan children with Burkitt lymphomas

Abstract: Key Points• Terminally differentiated CD56 neg NK cells expand in children after chronic malaria exposure and in those diagnosed with eBL.• NK cells in eBL patients express high levels of MIP-1b in lieu of TNF-a, and normal NK cell profiles appear to be restored in eBL survivors.

Cited by 44 publications

References 66 publications

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

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

Immune effector mechanisms in malaria: An update focusing on human immunity

Differential expression of maturation and activation markers on NK cells in patients with active and latent tuberculosis

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