Expression patterns of NKG2A, KIR, and CD57 define a process of CD56dim NK-cell differentiation uncoupled from NK-cell education

Björkström, Niklas K.; Riese, Peggy; Heuts, Frank; Andersson, Sandra; Fauriat, Cyril; Ivarsson, Martin A.; Björklund, Andreas; Flodström‐Tullberg, Malin; Michaëlsson, Jakob; Rottenberg, Martı́n E.; Guzmán, Carlos A.; Ljunggren, Hans‐Gustaf; Malmberg, Karl‐Johan

doi:10.1182/blood-2010-04-281675

Cited by 633 publications

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“…-1807 of highly functional NK cells. This is in accordance with published studies on human and murine NK cells, where mainly educated NK cells displayed functional capacities [16,46]. Although uneducated NK cells are considered to be hyporesponsive to ensure self-tolerance, they were described to be responsible for mCMV clearance [47].…”

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Activated NKT cells imprint NK‐cell differentiation, functionality and education

et al. 2015

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NK cells represent a vital component of the innate immune system. The recent discoveries demonstrating that the functionality of NK cells depends on their differentiation and education status underscore their potential as targets for immune intervention.However, to exploit their full potential, a detailed understanding of the cellular interactions involved in these processes is required. In this regard, the cross-talk between NKT cells and NK cells needs to be better understood. Our results provide strong evidence for NKT cell-induced effects on key biological features of NK cells. NKT-cell activation results in the generation of highly active CD27 high NK cells with improved functionality. In this context, degranulation activity and IFNγ production were mainly detected in the educated subset. In a mCMV infection model, we also demonstrated that NKT-cell stimulation induced the generation of highly functional educated and uneducated NK cells, crucial players in viral control. Thus, our findings reveal new fundamental aspects of the NKT-NK cell axis that provide important hints for the manipulation of NK cells in clinical settings.Keywords: αGalCerMPEG r mCMV r NK-cell differentiation r NK-cell education r NKT cells Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction NK cells represent a first line of defence against transformed or viral-infected cells by exerting immune regulatory and cytotoxic functions [1]. It was long believed that NK cells are a homogenous and short-lived innate lymphocyte population that retains their fixed phenotypic and functional characteristics. However, findings of a continuous NK-cell differentiation process at steadyCorrespondence: Dr. Peggy Riese e-mail: Peggy.Riese@helmholtz-hzi.de state conditions underscore their, up to now underestimated, multifunctional properties [2][3][4]. Several groups demonstrated that human and mouse NK cells represent a heterogeneous population that can be divided into different subsets with distinct functional properties [5][6][7][8]. In this context, CD27 and Mac-1 have been identified as key markers to dissect murine NK cells. CD27 high Mac-1 high NK cells display enhanced responsiveness, whereas the CD27 low Mac-1 high subset represents NK cells with a higher activation * These authors contributed equally to this work.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1794-1807 Innate immunity 1795 threshold [9,10]. The similarities between CD27 and Mac-1 expressing murine NK cells and human CD56 bright and CD56 dim NK-cell subsets enables a phenotypic and functional characterization comparable to the human system [11,12]. To ensure self-tolerance, NK-cell functionality is controlled by a process termed "education." Educated NK cells expressing inhibitory receptors binding to self-MHC molecules are more responsive to stimulation, whereas uneducated NK cells lacking self-MHC class I receptors are considered to be hypo-responsive [13][...

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Activated NKT cells imprint NK‐cell differentiation, functionality and education

et al. 2015

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“…Additionally, NK cell KIR expression is related to cellular differentiation. KIR expression is weak or absent in immature NKG2A + CD56 bright NK cells and increases gradually with maturation, reaching its maximum level in NKG2A − CD56 dim NK cells 148, 149, 150. Similar observation was made for T cells, in which KIR expression is virtually absent in CD4 and CD8 naive T cells and reaches its maximal level in differentiated effector memory T cells 2, 5, 151, 152.…”

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confidence: 68%

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

et al. 2016

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SummaryKiller‐cell immunoglobulin‐like receptors (KIRs) are components of two fundamental biological systems essential for human health and survival. First, they contribute to host immune responses, both innate and adaptive, through their expression by natural killer cells and T cells. Second, KIR play a key role in regulating placentation, and hence reproductive success. Analogous to the diversity of their human leucocyte antigen class I ligands, KIR are extremely polymorphic. In this review, we describe recent developments, fuelled by methodological advances, that are helping to decipher the KIR system in terms of haplotypes, polymorphisms, expression patterns and their ligand interactions. These developments are delivering deeper insight into the relevance of KIR in immune system function, evolution and disease.

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“…53 On the other hand, in line with their high content of perforin/granzyme and their high expression of CD16, PD-1 1 NK cells could degranulate to levels comparable with PD-1 2 cells in response to anti-CD16 mAbs in R-ADCC. [50][51][52] Thus under this experimental condition, the impaired degranulation of PD-1 1 NK cells caused by downregulation of NCRs (NKp30 and NKp46) can be bypassed by a potent stimulus delivered by CD16. Based on the recovery of different functions (cytokine release and cytotoxicity) on cell triggering through CD16 in R-ADCC, it is unlikely that PD-1 1 NK cells merely represent a population of exhausted cells with an intrinsic functional defect.…”

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confidence: 89%

Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization

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et al. 2017

Journal of Allergy and Clinical Immunology

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Background: Programmed death 1 (PD-1) is an immunologic checkpoint that limits immune responses by delivering potent inhibitory signals to T cells on interaction with specific ligands expressed on tumor/virus-infected cells, thus contributing to immune escape mechanisms. Therapeutic PD-1 blockade has been shown to mediate tumor eradication with impressive clinical results. Little is known about the expression/function of PD-1 on human natural killer (NK) cells. Objective: We sought to clarify whether human NK cells can express PD-1 and analyze their phenotypic/functional features. Methods: We performed multiparametric cytofluorimetric analysis of PD-1 1 NK cells and their functional characterization using degranulation, cytokine production, and proliferation assays. Results: We provide unequivocal evidence that PD-1 is highly expressed (PD-1 bright ) on an NK cell subset detectable in the peripheral blood of approximately one fourth of healthy subjects. These donors are always serologically positive for human cytomegalovirus. PD-1 is expressed by CD56 dim but not CD56 bright NK cells and is confined to fully mature NK cells characterized by the NKG2A 2 KIR 1 CD57 1 phenotype. Proportions of PD-1 bright NK cells were higher in the ascites of a cohort of patients with ovarian carcinoma, suggesting their

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Expression patterns of NKG2A, KIR, and CD57 define a process of CD56dim NK-cell differentiation uncoupled from NK-cell education

Cited by 633 publications

References 51 publications

Activated NKT cells imprint NK‐cell differentiation, functionality and education

Activated NKT cells imprint NK‐cell differentiation, functionality and education

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization

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