Identification, activation, and selective<i>in vivo</i>ablation of mouse NK cells via NKp46

Walzer, Thierry; Bléry, Mathieu; Chaix, Julie; Fuséri, Nicolas; Chasson, Lionel; Robbins, Scott H.; Jaeger, Sébastien; Pèlegrin, André; Gauthier, Laurent; Daniel, Laurent; Chemin, Karine; Morel, Yannis; Dalod, Marc; Imbert, Jean; Pierres, Michel; Moretta, Alessandro; Romagné, François; Vivier, Éric

doi:10.1073/pnas.0609692104

Cited by 413 publications

(428 citation statements)

References 50 publications

(47 reference statements)

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“…However, in spleen as well as in peripheral lymph nodes, B and T cells can interact during migration from the peripheral blood. Since splenic NK cells predominantly are located in the red pulp and thus maintain less cell-cell contacts with B cells [34], our results suggest that even without abundant cell-cell interactions, CD27 on NK cells is triggered sufficiently by CD70 to result in reduced receptor expression. Alternatively, CD27 down-regulation can be induced in the BM where cell-cell contacts between NK and B cells probably occur more frequently.…”

Section: Discussionmentioning

confidence: 81%

Continuous CD27 triggering in vivo strongly reduces NK cell numbers

et al. 2010

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NK cells are important mediators of the early defense. In mice, immature and mature NK (mNK) cells constitutively express the TNF receptor family member CD27; however, mNK cells eventually lose CD27 expression and become resting NK cells. Interaction of CD27 with its ligand, CD70, enhances proliferation and effector functions of NK cells. We used mice that constitutively express CD70 on B cells (CD70-Tg) to study the in vivo effects of continuous triggering of CD27 on NK cells. Continuous CD70-CD27 interaction resulted in strongly down-modulated CD27 expression on NK cells and gradually reduced absolute NK cell numbers. This reduction was most prominent in the mNK cell subpopulation and was at least partially due to increased apoptosis. Residual NK cells showed lower expression of activating Ly49 receptors and normal (liver) or decreased (spleen) IFN-c production. Nevertheless, NK cells from CD70-Tg mice displayed higher YAC-1 killing capacities. CD70-Tg NK cells exhibited up-regulated expression of NKG2D, which is in accordance with the increased YAC-1 lysis, as this is mainly NKG2D-dependent. Taken together, this study is the first to demonstrate that continuous CD70 triggering of CD27 on NK cells in vivo results in a severe reduction of NK cells. On a single cell basis, however, residual NK cells display enhanced cytotoxicity.Key words: CD70-Tg mice . Cytotoxicity . Differentiation Supporting Information available online Introduction NK cells are large granular lymphocytes of the innate immune system that play a crucial role in the early host defense [1,2]. Upon activation, they directly eliminate target cells through exocytosis of perforin-and granzyme-containing granules, or by Fas ligand (CD178) or TRAIL pathways [3][4][5][6][7]. NK cells also produce cytokines and chemokines, which enable them to recruit non-specific haematopoetic cells, activate dendritic cells and prime adaptive lymphocytes [8][9][10][11]. As such, NK cells bridge between innate and adaptive immunity. The functional behaviour of NK cells is regulated by the engagement of a broad array of activating and inhibitory cell membrane receptors (reviewed in Lanier [12]).The BM is considered to be the main site for NK cell development [13][14][15][16]. Here, multipotent haematopoietic precursors generate NK cell precursors (NKP). Murine NKP are lineage(lin) À CD122 1 NK1.1 À CD49b À . NKP differentiate into immature NK (iNK) cells, which exhibit a lin À CD122 1 NK1. [20,21]. Interestingly, Hayakawa and Smyth [22]showed that within the TCR b À NK1.1 1 gated NK cell pool there is a CD11b low subpopulation, including both iNK and early mNK cells, which is homogenously CD27 high (referred to as subset 1), whereas the CD11b high population of late mNK cells consists of two functionally distinct subsets: i.e. CD27 high (referred to as subset 2) and CD27 low (referred to as subset 3). NK cells from subset 1 are the first NK cell population detected after BM transplantation and they give rise to subset 2 after adoptive transfer. Subset 2 consists of fu...

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Section: Discussionmentioning

confidence: 81%

Continuous CD27 triggering in vivo strongly reduces NK cell numbers

et al. 2010

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“…However, during analyses of these types of systems, it was noticed that Ly5.1 + mice consistently exhibited very poor expression of the receptor NKp46, a key phenotypic marker of NK cells 22 and some subsets of ILCs, in multiple tissues including peripheral blood (Figure 1A), bone marrow, peripheral lymph nodes and spleen (Figure 1B). This observation was made in two mouse colonies completely independent of each other but which were originally derived from the Jackson Laboratory (Jax) imported in 2008 (University Hospital Erlangen) and 2010 (Walter and Eliza Hall Institute, WEHI) and maintained as closed colonies.…”

Section: Resultsmentioning

confidence: 99%

A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets

et al. 2018

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NKp46 (CD335) is a surface receptor shared by both human and mouse natural killer (NK) cells and innate lymphoid cells (ILCs) that transduces activating signals necessary to eliminate virus-infected cells and tumors. Here, we describe a spontaneous point mutation of cysteine to arginine (C14R) in the signal peptide of the NKp46 protein in congenic Ly5.1 mice and the newly generated NCRB6C14R strain. Ly5.1C14R NK cells expressed similar levels of Ncr1 mRNA as C57BL/6, but showed impaired surface NKp46 and reduced ability to control melanoma tumors in vivo. Expression of the mutant NKp46C14R in 293T cells showed that NKp46 protein trafficking to the cell surface was compromised. Although Ly5.1C14R mice had normal number of NK cells, they showed an increased number of early maturation stage NK cells. CD49a+ILC1s were also increased but these cells lacked the expression of TRAIL. ILC3s that expressed NKp46 were not detectable and were not apparent when examined by T-bet expression. Thus, the C14R mutation reveals that NKp46 is important for NK cell and ILC differentiation, maturation and function.SignificanceInnate lymphoid cells (ILCs) play important roles in immune protection. Various subsets of ILCs express the activating receptor NKp46 which is capable of recognizing pathogen derived and tumor ligands and is necessary for immune protection. Here, we describe a spontaneous point mutation in the signal peptide of the NKp46 protein in congenic Ly5.1 mice which are widely used for tracking cells in vivo. This Ncr1 C14R mutation impairs NKp46 surface expression resulting in destabilization of Ncr1 and accumulation of NKp46 in the endoplasmic reticulum. Loss of stable NKp46 expression impaired the maturation of NKp46+ ILCs and altered the expression of TRAIL and T-bet in ILC1 and ILC3, respectively.

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“…Few NK1.1 -cd T cells expressed these receptors, but NK1.1 + cd T cells (with higher levels of CD3/CD5 than NK-like cd T cells) had an intermediate phenotype. Amongst the molecules tested, NKp46 showed the greatest NK specificity [21]. NKp46 expression by NK-like cd T cells therefore highlights the extent of their NK programming, as it was present on 60% of NK-like cd T cells (Fig.…”

mentioning

confidence: 88%

“…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].…”

Section: Introductionmentioning

confidence: 99%

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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Identification, activation, and selectivein vivoablation of mouse NK cells via NKp46

Cited by 413 publications

References 50 publications

Continuous CD27 triggering in vivo strongly reduces NK cell numbers

Continuous CD27 triggering in vivo strongly reduces NK cell numbers

A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets

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

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