'Unlicensed' natural killer cells dominate the response to cytomegalovirus infection

Orr, Mark T.; Murphy, William J.; Lanier, Lewis L.

doi:10.1038/ni.1849

Cited by 247 publications

(271 citation statements)

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“…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]. The results obtained here contribute toward the understanding of this apparent dilemma.…”

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confidence: 79%

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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confidence: 79%

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

et al. 2015

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“…Most of the IFN-␥ produced during MCMV infection originates from "unlicensed" Ly49C/Inegative NK cells. 35 For personal use only. on May 12, 2018.…”

Section: Discussionmentioning

confidence: 99%

Impaired natural killer cell self-education and “missing-self” responses in Ly49-deficient mice

Bélanger

Rahim

et al. 2012

Blood

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Ly49-mediated recognition of MHC-I molecules on host cells is considered vital for natural killer (NK)–cell regulation and education; however, gene-deficient animal models are lacking because of the difficulty in deleting this large multigene family. Here, we describe NK gene complex knockdown (NKCKD) mice that lack expression of Ly49 and related MHC-I receptors on most NK cells. NKCKD NK cells exhibit defective killing of MHC-I–deficient, but otherwise normal, target cells, resulting in defective rejection by NKCKD mice of transplants from various types of MHC-I–deficient mice. Self–MHC-I immunosurveillance by NK cells in NKCKD mice can be rescued by self–MHC-I–specific Ly49 transgenes. Although NKCKD mice display defective recognition of MHC-I–deficient tumor cells, resulting in decreased in vivo tumor cell clearance, NKG2D- or antibody-dependent cell-mediated cytotoxicity–induced tumor cell cytotoxicity and cytokine production induced by activation receptors was efficient in Ly49-deficient NK cells, suggesting MHC-I education of NK cells is a single facet regulating their total potential. These results provide direct genetic evidence that Ly49 expression is necessary for NK-cell education to self–MHC-I molecules and that the absence of these receptors leads to loss of MHC-I–dependent “missing-self” immunosurveillance by NK cells.

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“…Inhibitory NK cell receptors might function as checkpoints to control different steps in the generation of memory cells. LY49H + NK cells that lack inhibitory LY49 receptors and recognize self-MHC class I ligands preferentially respond during the expansion phase following MCMV infection 31 . Whether CD96 (also known as TACTILE) and T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) 32 , two inhibitory receptors that bind to the DNAM1 ligand CD155 and counteract NK cell activation, control the formation of memory NK cell populations has not been determined.…”

Section: Box 1 | Memory In Myeloid Cells In Mammalsmentioning

confidence: 99%

Natural killer cell memory in infection, inflammation and cancer

2016

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| Immunological memory can be defined as a quantitatively and qualitatively enhanced immune response upon rechallenge. For natural killer (NK) cells, two main types of memory exist. First, similarly to T cells and B cells, NK cells can exert immunological memory after encounters with stimuli such as haptens or viruses, resulting in the generation of antigen-specific memory NK cells. Second, NK cells can remember inflammatory cytokine milieus that imprint long-lasting non-antigen-specific NK cell effector function. The basic concepts derived from studying NK cell memory provide new insights about innate immunity and could lead to novel strategies to improve treatments for infectious diseases and cancer.

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'Unlicensed' natural killer cells dominate the response to cytomegalovirus infection

Cited by 247 publications

References 50 publications

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

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

Impaired natural killer cell self-education and “missing-self” responses in Ly49-deficient mice

Natural killer cell memory in infection, inflammation and cancer

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