Clonal analysis of NK cell development from bone marrow progenitors
            <i>in vitro</i>
            : orderly acquisition of receptor gene expression

Williams, Noelle S.; Kubota, Akira; Bennett, Michael V. L.; Kumar, Vinay; Takei, Fumio

doi:10.1002/1521-4141(200007)30:7<2074::aid-immu2074>3.0.co;2-#

Cited by 82 publications

(74 citation statements)

References 21 publications

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“…Stromal cells contain at least two key factors that are essential for NK cell maturation, i.e., LT␤R, which interacts with the membrane-bond form of LT (LT␣1␤ 2 ) (67) and the cytokine IL-15 (69). In particular, IL-15 secreted from the stromal cells has been implicated both in the early commitment phase of the NKPs and during the Ly49C acquisition at preterminal maturation phase.…”

Section: Discussionmentioning

confidence: 99%

Differential and Nonredundant Roles of Phospholipase Cγ2 and Phospholipase Cγ1 in the Terminal Maturation of NK Cells

Regunathan

Chen

Kutlesa

et al. 2006

The Journal of Immunology

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NK cells play a central role in mediating innate immune responses. Activation of NK cells results in cytotoxicity, cytokine, and chemokine secretions. In this study, we show that in mice with targeted deletion of phospholipase Cγ (PLCγ)2, one of the key signal transducers, there are profound effects on the development and terminal maturation of NK cells. Lack of PLCγ2 significantly impaired the ability of lineage-committed NK precursor cells to acquire subset-specific Ly49 receptors and thereby terminal maturation of NK cells. Overexpression of isozyme, PLCγ1, in PLCγ2-deficient NK cells resulted in the successful Ly49 acquisition and terminal maturation of the NK cells; however, it could only partially rescue NKG2D-mediated cytotoxicity with no cytokine production. Furthermore, PLCγ2-deficient NK cells failed to mediate antitumor cytotoxicity and inflammatory cytokine production, displaying a generalized hyporesponsiveness. Our results strongly demonstrate that PLCγ1 and PLCγ2 play nonredundant and obligatory roles in NK cell ontogeny and in its effector functions.

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Section: Discussionmentioning

confidence: 99%

Differential and Nonredundant Roles of Phospholipase Cγ2 and Phospholipase Cγ1 in the Terminal Maturation of NK Cells

Regunathan

Chen

Kutlesa

et al. 2006

The Journal of Immunology

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“…Data presented to date are consistent with both of these models. Recent data from two in vitro cell culture systems suggest that NK cells begin to express different Ly49 receptors at different times during their development, although the order of receptor expression differed between the two systems (49,50). The sequential and selection models make different predictions about how expression of a single Ly49 receptor on all NK cells would alter the repertoire development.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro data suggest that there may be a time element that needs to be considered (49,50). During NK cell differentiation, there may be a discrete stage in which Ly49 receptor genes can be activated.…”

Section: Discussionmentioning

confidence: 99%

“…As we have discussed, there are several elements that together explain Ly49 receptor expression and regulation in addition to the direct interaction between Ly49 receptors and MHC class I molecules. Ly49A and Ly49D are known to be regulated by a specific transcription factor, and in vitro data suggest that they may be expressed after Ly49C and Ly49G2 (50,56). It is possible that Ly49 receptors can interact with other molecules in the absence of ␤ 2 m, such as MHC class I free heavy chains or nonclassical MHC molecules, and these interactions may alter expression of some Ly49 receptors.…”

Section: Discussionmentioning

confidence: 99%

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MHC Class I-Ly49 Interactions Shape the Ly49 Repertoire on Murine NK Cells

Fahlén

Lendahl

Sentman

2001

The Journal of Immunology

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This study aims to determine how the interaction of Ly49 receptors with MHC class I molecules shapes the development of the Ly49 repertoire. We have examined the percentage of NK cells that expressed Ly49A, Ly49G2, and Ly49D in single and double Ly49A/C-transgenic mice on four different MHC backgrounds, H-2b, H-2d, H-2b/d, and β2-microglobulin−/−. The results show that the total numbers of NK cells were not different among the strains. The prior expression of a Ly49 receptor capable of binding to self MHC class I altered the percentage of NK cells expressing endogenous Ly49A, Ly49G2, and Ly49D even in mice in which no MHC ligand was present for the latter receptors. The NK cells in the Ly49-transgenic mice expressed the same level of endogenous Ly49 receptors as wild-type mice of a similar MHC background. In contrast, the number of NK T cells was reduced in mice in which the Ly49 transgene could bind to a MHC class I molecule. The onset of Ly49 receptor expression on NK cells during ontogeny was not altered in the presence of transgenic Ly49 receptors. These data support a sequential model and argue against a selection model for Ly49 repertoire development on NK cells.

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“…Rag-deficient mice were used to facilitate identification of cell populations in the bone marrow, and to restrict our study to that of germ-line Tcrd transcription. Developing NK cells in the bone marrow of Rag-deficient Tcrd-H2BEGFP mice were divided into NK precursors (CD122 + NK1.1 -DX5 -), immature NK (CD122 + NK1.1 + DX5 -) and mature (CD122 + NK1.1 + DX5 + ) NK cell populations according to current models [23,[35][36][37].…”

Section: Germ-line Tcrd-egfp Expression Initiates During Nk Maturationmentioning

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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Clonal analysis of NK cell development from bone marrow progenitors in vitro : orderly acquisition of receptor gene expression

Cited by 82 publications

References 21 publications

Differential and Nonredundant Roles of Phospholipase Cγ2 and Phospholipase Cγ1 in the Terminal Maturation of NK Cells

Differential and Nonredundant Roles of Phospholipase Cγ2 and Phospholipase Cγ1 in the Terminal Maturation of NK Cells

MHC Class I-Ly49 Interactions Shape the Ly49 Repertoire on Murine NK Cells

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

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