Human NK Cell Education by Inhibitory Receptors for MHC Class I

Anfossi, Nicolas; Pèlegrin, André; Guia, Sophie; Falk, Christine S.; Roetynck, Sophie; Stewart, Charles A.; Breso, Violette; Frassati, Coralie; Reviron, D; Middleton, Derek; Romagné, François; Ugolini, Sophie; Vivier, Éric

doi:10.1016/j.immuni.2006.06.013

Cited by 1,022 publications

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References 41 publications

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“…Several in vivo data provided a hint that hyporesponsive NK cells that do not express inhibitory receptors can still function during infectious diseases [4,8]. Besides, it has been controversially discussed whether IL-2 stimulation could reverse NK-cell hyporesponsiveness [5,10]. In our system, only acquisition of self-MHC-specific KIR (i.e.…”

Section: Discussionmentioning

confidence: 97%

“…2). Our findings support the concept that, once a KIR is acquired, even after in vitro cytokine stimulation, its expression remains stable.Acquisition of self-specific KIR confers functional competence an CD56 dim KIR À NKG2A -NK cells Since ex vivo expression of self-specific inhibitory receptors correlates with NK-cell functional competence [5,6], we wanted to evaluate whether acquisition of KIR expression after cytokine stimulation confers competence on CD56 dim KIR À NKG2A À hyporesponsive NK cells and whether engagement of self-MHC is required. To answer these questions, KIR3DL1 expression was induced in CD56 dim KIR À NKG2A À NK cells from HLA-Bw4 or HLA-Bw6 individuals that do or do not express the cognate MHC ligand for KIR3DL1, respectively.…”

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confidence: 99%

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Education of hyporesponsive NK cells by cytokines

et al. 2009

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NK-cell tolerance to self is mediated via engagement of inhibitory receptors by cognate MHC molecules. This event is critical for NK-cell education to achieve functional competence. Thus, NK cells expressing self-MHC-specific inhibitory receptors are responsive to activating stimuli while those lacking such receptors are hyporesponsive. Nevertheless, the mechanisms underlying NK-cell education are still poorly understood. Here, we show that after stimulation with cytokines, hyporesponsive NK cells acquire stable expression of killer Ig-like receptors (KIR) as reflected by DNA hypomethylation of their KIR locus. Remarkably, only hyporesponsive NK cells that acquire KIR in the presence of their cognate MHC molecule gain functional competence and this process can occur in the absence of any accessory cells. Acquisition of competence does not result in autoreactivity, since acquired KIR are functional and therefore able to inhibit NK-cell cytotoxicity. Our data demonstrate that competent NK cells can be generated by cytokine stimulation, suggesting that NK-cell education might not only be an early event which takes place during NK-cell development but might also occur in the periphery during an immune response.Key words: Education . Killer Ig-like receptors . MHC . NK cells . Tolerance Supporting Information available onlineIntroduction NK cells are bone-marrow derived lymphocytes which play an important role in mediating innate immune responses to viruses, tumors and MHC-mismatched bone marrow grafts. The main effector functions of NK cells, such as cytokine production and cytotoxicity, are tightly regulated by a balance between activating and inhibitory signals. After engagement of multiple activating receptors expressed on their surface, NK cells can produce IFN-g and kill target cells. In most cases, ligands for activating receptors are pathogen-encoded molecules or self-proteins whose expression is up-regulated in transformed or infected cells. However, even normal cells can be lysed by NK cells if they fail to express a full set of self-MHC class I proteins [1]. These observations highlight NK-cell potential autoreactivity and raise the question of how NK cells discriminate diseased cells from healthy ones. NK cells are self-tolerant because they express inhibitory receptors specific for distinct polymorphic variants of MHC class I molecules which counteract the activating signals. Inhibitory receptors include the killer Ig-like receptors (KIR) in humans, the lectin-like Ly49 dimers in mice and the lectin-like CD94/NKG2A heterodimers in both species. Interestingly, the genes for inhibitory receptors and their cognate MHC class I ligands segregate independently, so genetic mechanisms cannot ensure that each NK-cell inhibitory receptor encounters its specific self-MHC class I molecule [2]. In line with this fact, some NK cells exist, which do not express any self-MHC class I-specific inhibitory receptor. However, 2548such NK cells are self-tolerant because they are hyporesponsive after engagement of activating ...

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Section: Discussionmentioning

confidence: 97%

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Education of hyporesponsive NK cells by cytokines

et al. 2009

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“…These features, together with high expression of cytolytic molecules, allow CD56 dim NK cells to efficiently lyse target cells either directly or indirectly through CD16‐mediated antibody‐dependent cellular cytotoxicity (ADCC). The expression of a family of receptors called killer immunoglobulin‐like receptors (KIRs), which modulate the responsiveness of NK cells to activating receptor ligation,62, 63 is also restricted to CD56 dim NK cells.…”

Section: Subsets Of Nk Cellsmentioning

confidence: 99%

Innate‐like CD8+ T‐cells and NK cells: converging functions and phenotypes

2018

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SummaryNew data in the worlds of both innate‐like CD8+ T‐cells and natural killer (NK) cells have, in parallel, clarified some of the phenotypes of these cells and also their associated functions. While these cells are typically viewed entirely separately, the emerging innate functions of T‐cells and, similarly, the adaptive functions of NK cells suggest that many behaviours can be considered in parallel. In this review we compare the innate functions of CD8+ T‐cells (especially mucosal‐associated invariant T‐cells) and those of NK cells, and how these relate to expression of phenotypic markers, especially CD161 and CD56.

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“…At the immature DX5 -stage, NK cells express multiple NK receptors including CD94/NKG2, NKG2D and NKp46, but are unable to perform granule-mediated cytotoxicity [21][22][23]. During maturation to DX5 + mature cells, NK cells start to express Ly49 MHC class I receptors [22][23][24], and undergo an education process during which NK cells expressing inhibitory receptors that recognize self MHC class I are "licensed" to perform more potent effector functions [25][26][27][28].cd T cells, like ab T cells, develop in the thymus, where V(D)J recombination of TCR genes occurs. Using T cell receptor d locus-histone 2B-enhanced GFP (Tcrd-H2BEGFP) knock-in mice in which an IRES-controlled H2B-EGFP fusion protein is present in the 3 0 untranslated region of the Tcrd constant gene [29], we have recently shown that developing cd T cells undergo a "TCR quality control checkpoint" upon successful expression of TCRcd.…”

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Germ‐line and rearranged Tcrd transcription distinguish bona fide NK cells and NK‐like γδ T cells

et al. 2007

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NK cells and cd T cells are distinct subsets of lymphocytes that contextually share multiple phenotypic and functional characteristics. However, the acquisition and the extent of these similarities remain poorly understood. Here, using T cell receptor d locus-histone 2B-enhanced GFP (Tcrd-H2BEGFP) reporter mice, we show that germline transcription of Tcrd occurs in all maturing NK cells. We also describe a population of mouse NK-like cells that are indistinguishable from "bona fide" NK cells using standard protocols. Requirements for V(D)J recombination and a functional thymus, along with very low-level expression of surface TCRcd but high intracellular CD3, define these cells as cd T cells. "NK-like cd T cells" are CD127 + , have a memory-activated phenotype, express multiple NK cell receptors and readily produce interferon-c in response to IL-12/IL-18 stimulation. The close phenotypic resemblance between NK cells and NK-like cd T cells is a source of experimental ambiguity in studies bridging NK and T cell biology, such as those on thymic NK cell development. Instead, it ascribes chronic TCRcd engagement as a means of acquiring NK-like function. IntroductionClassification of NK cells and some cd T cell subsets as innate immune cells is argued by their recognition and response to self ligands and microbial molecules without any requirement for prior specific immunization [1][2][3][4][5]. NK cells are mediators of immunity against various infectious diseases and tumor cells, performing direct cell-mediated cytotoxicity and producing cytokines in response to cell-associated and soluble stimuli [6,7]. They additionally shape adaptive immune responses, mainly through the production of cytokines [8]. Their activation is regulated through germ-line-encoded receptors including NKG2D, the natural cytotoxicity receptors and inhibitory receptors for MHC class I, many of which recognize self-encoded ligands [9][10][11]. Most cd T cell subsets are unconventional T cells that -similar to CD1d-restricted Va14i NKT cells, MR1-restricted MAIT cells and certain populations of CD8 + T cells -are not restricted to classical MHC class I-or MHC class II-bearing specific peptides [2,3]. They have heterogeneous effector functions associated with differential TCRcd usage. Roles have been described in immunity against infectious pathogens and tumors [12] and cd T cells have been strongly implicated in immunosuppressive regulation of the immune system and in the process of wound healing [13,14]. Using TCR transfer experiments, or direct ligand binding, TCRcd ligands have been described for a small number of subsets [5]. In the mouse, cd T cell subsets recognize the non-classical MHC class I molecules T10/T22 [15], and an unknown ligand expressed by keratinocytes [16]. In humans, some Vd1 cd T cells recognize non-classical MHC class I molecules MICA and MICB, and Vc9Vd2 cd T cells have been reported to recognize self and bacterial phosphoantigens, and a complex formed between F1-ATP synthase and apolipoprotein A-1 [5,[17][18][19][20].Du...

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Human NK Cell Education by Inhibitory Receptors for MHC Class I

Cited by 1,022 publications

References 41 publications

Education of hyporesponsive NK cells by cytokines

Education of hyporesponsive NK cells by cytokines

Innate‐like CD8+ T‐cells and NK cells: converging functions and phenotypes

Germ‐line and rearranged Tcrd transcription distinguish bona fide NK cells and NK‐like γδ T cells

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