Adaptive NK cells can persist in patients with GATA2 mutation depleted of stem and progenitor cells

Schlums, Heinrich; Jung, Moonjung; Han, Hongya; Theorell, Jakob; Bigley, Venetia; Chiang, Samuel C.C.; Allan, David; Davidson-Moncada, Jan K.; Dickinson, Rachel; Holmes, Tim D.; Hsu, Amy P.; Townsley, Danielle M.; Winkler, Thomas; Wang, Weixin; Aukrust, Pål; Nordøy, Ingvild; Calvo, Katherine R.; Holland, Steve; Collin, Matthew; Dunbar, Cynthia E.; Bryceson, Yenan T.

doi:10.1182/blood-2016-08-734236

Cited by 66 publications

(62 citation statements)

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“…These adaptive NK cell populations have been mostly extensively characterized in the settings of murine cytomegalovirus (MCMV) and HCMV (Hammer and Romagnani, 2017; Tesi et al, 2016). Indeed adaptive NK cells show an array of functional, phenotypic, epigenetic, and homeostatic differences from cNK cells that warrant their classification as a subset distinct from cNK cells (Corat et al, 2017; Hwang et al, 2012; Schlums et al, 2015; Schlums et al, 2017). …”

Section: Adaptive Nk Cellsmentioning

confidence: 99%

“…It remains to be seen if in vivo co-stimulation alters adaptive NK cell functionality (Liu et al, 2016). Lastly, recent studies involving patients with either paroxysmal nocturnal hemoglobinuria or GATA2 deficiency indicate that adaptive NK cells selectively persist in these patients whereas cNK cells are reduced, indicative of unique homeostatic regulatory mechanisms at play (Corat et al, 2017; Schlums et al, 2017). Therefore, adaptive NK cells are very distinct in multiple aspects of their basic biology, implying that they fulfill distinct role(s) in immunity.…”

Section: Adaptive Nk Cellsmentioning

confidence: 99%

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The Broad Spectrum of Human Natural Killer Cell Diversity

et al. 2017

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SUMMARY Natural killer (NK) cells provide protection against infectious pathogens and cancer. For decades it has been appreciated that two major NK cell subsets (CD56bright and CD56dim) exist in humans and have distinct anatomical localization patterns, phenotypes, and functions in immunity. In light of this traditional NK cell dichotomy, it is now clear that the spectrum of human NK cell diversity is much broader than originally appreciated as a result of variegated surface receptor, intracellular signaling molecule, and transcription factor expression; tissue-specific imprinting; and foreign antigen exposure. The recent discoveries of tissue-resident NK cell developmental intermediates, non-NK innate lymphoid cells, and the capacity for NK cells to adapt and differentiate into long-lived memory cells has added further complexity to this field. Here we review our current understanding of the breadth and generation of human NK cell diversity.

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Section: Adaptive Nk Cellsmentioning

confidence: 99%

Section: Adaptive Nk Cellsmentioning

confidence: 99%

The Broad Spectrum of Human Natural Killer Cell Diversity

et al. 2017

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“…However, it is still unclear how a CD56 bright NK cell may undergo differentiation to a CD56 dim cell, both in terms of regulation of CD56 itself and also the host of receptors and functions associated with this transition. The role that GATA2 plays in NK cell homeostasis can be explained by the finding that the remaining CD56 dim NK cells in GATA2‐deficient patients have an adaptive phenotype identified by down‐regulation of SYK, EAT2, PLZF1, and/or FcεGRγ, suggesting that these are long‐lived and that conventional NK cells have been lost from circulation due to attrition of stem cell precursors from the bone marrow . In addition, there may be effects on NK cell trafficking, given the loss of CXCR4 expression on NK cells from GATA2‐deficient patients .…”

Section: Classical Nkd (Cnkd)mentioning

confidence: 99%

“…Regardless, 82% of patients experienced major infections, and of these, 70% are herpesviral infections that are commonly one of the earliest clinical features of disease . There additionally is a correlation between decreasing NK cell numbers in the periphery and increasing complications of disease, and asymptomatic carriers of GATA2 mutations are often CMV seronegative and have higher frequencies of NK cells in peripheral blood . Taken together, these observations suggest that viral infection in the face of impaired NK cell homeostasis and function contributes to NK cell attrition and progression of disease.…”

Section: Classical Nkd (Cnkd)mentioning

confidence: 99%

“…The identification of a persistent adaptive NK cell population in GATA2‐deficient patients highlights the distinct longevity of these cells and suggests that there may be other cases whether the generation of adaptive cells is either impaired, or where the progressive loss of non‐adaptive cells leads to their selective survival. Identifying an NKD with a specific deficit in adaptive or memory‐like NK cell generation would be informative in understanding their role in control of viral infection and malignancy.…”

Section: Emerging Themes In Nk Cell Deficiencymentioning

confidence: 99%

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Emerging insights into human health and NK cell biology from the study of NK cell deficiencies

Mace

Orange

2018

Immunological Reviews

133

107

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Human NK cells are innate immune effectors that play a critical roles in the control of viral infection and malignancy. The importance of their homeostasis and function can be demonstrated by the study of patients with primary immunodeficiencies (PID), which are part of the family of diseases known as inborn defects of immunity. While NK cells are affected in many PIDs in ways that may contribute to a patient’s clinical phenotype, a small number of PIDs have an NK cell abnormality as their major immunological defect. These PIDs can be collectively referred to as NK cell deficiency disorders (NKD), and include effects upon NK cell numbers, subsets and/or functions. The clinical impact of NKD can be severe including fatal viral infection, with particular susceptibility to herpesviral infections, such as cytomegalovirus, varicella zoster virus and Epstein-Barr virus. While NKD is rare, studies of these diseases are important for defining specific requirements for human NK cell development and homeostasis. New themes in NK cell biology are emerging through the study of both known and novel NKD, particularly those affecting cell cycle and DNA damage repair, as well as broader PIDs having substantive impact upon NK cells. In addition, the discovery of NKD that affect other innate lymphoid cell (ILC) subsets opens new doors for better understanding the relationship between conventional NK cells and other ILC subsets. Here we describe the biology underlying human NKD, particularly in the context of new insights into innate immune cell function, including a discussion of recently described NKD with accompanying effects on ILC subsets. Given the impact of these disorders upon human immunity with a common focus upon NK cells, the unifying message of a critical role for NK cells in human host defense singularly emerges.

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CMV and natural killer cells: shaping the response to vaccination

et al. 2017

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Cytomegaloviruses (CMVs) are highly prevalent, persistent human pathogens that not only evade but also shape our immune responses. Natural killer (NK) cells play an important role in the control of CMV and CMVs have in turn developed a plethora of immunoevasion mechanisms targeting NK cells. This complex interplay can leave a long-lasting imprint on the immune system in general and affect responses toward other pathogens and vaccines. This review aims to provide an overview of NK cell biology and development, the manipulation of NK cells by CMVs and the potential impact of these evasion strategies on responses to vaccination.Keywords: CMV r HCMV r Immune evasion r NK cells r Vaccination IntroductionCytomegaloviruses (CMVs) are beta-herpesviruses that establish life-long persistent infection of their hosts. After resolution of acute infection, the virus enters a state of latency during which very few genes are transcribed and no new viral progeny are being generated. Latency is interrupted by occasional reactivations of the virus and expression of genes associated with the lytic virus lifecycle [1]. The success of CMVs as pathogens is a consequence of multiple immunoevasion mechanisms such as downregulation of immunoreceptor ligands or expression of decoy molecules that they employ against every arm of the immune system, including NK cells, which play an important role in the early control of virally infected and malignant cells [2]. Individuals lacking NK cells may suffer from recurrent virus infections, most commonly caused by herpes viruses and papilloma viruses, as well as increased susceptibility to malignant tumors [3][4][5]. However, in other cases, there is no obvious clinical immunodeficiency associated with the Correspondence: Dr. Vanda Juranić Lisnić e-mail: vanda.juranic@medri.uniri.hr absence of NK cells, indicating redundancy with other immune compartments for distinct genetic deficiencies [6,7]. As NK cells also regulate other arms of the immune response, their modulation by CMV can have broader consequences for immunity [8]. For instance, the strength of the primary NK cell response against the virus can have a significant impact on the adaptive immune response, although the underlying mechanisms for this are not yet clear and vary according to host and virus genotypes [9,10]. CMV infection is associated with expansion of effector memory CD8 T cell clones that are sustained for the lifetime of the host and can comprise a significant percentage of the total CD8 T cell population in aging individuals [11]. Multiple lines of evidence in experimental animals and in humans which will be discussed in this review, now indicate that CMV infection leaves a similar long-lasting imprint on NK cell phenotype and function, affecting NK cell responses to other pathogens and to vaccination.Vaccines facilitate control and eradication of infectious diseases that have plagued humanity for centuries but new infections, * Current address: Eleanor M. Riley NK cell activity depends on a balance of signals from inhibit...

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Adaptive NK cells can persist in patients with GATA2 mutation depleted of stem and progenitor cells

Abstract: Key Points GATA-2 expression is restricted to hematopoietic stem and progenitor cells, leading to NK-cell progenitor deficiency in GATA2 patients. A long-lived or self-renewing pool of adaptive NK cells can persist in patients with GATA2 mutation.

Cited by 66 publications

References 65 publications

The Broad Spectrum of Human Natural Killer Cell Diversity

The Broad Spectrum of Human Natural Killer Cell Diversity

Emerging insights into human health and NK cell biology from the study of NK cell deficiencies

CMV and natural killer cells: shaping the response to vaccination

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