Expression of IFN-γ Upon Triggering of Activating Ly49D NK Receptors In Vitro and In Vivo: Costimulation with IL-12 or IL-18 Overrides Inhibitory Receptors

Ortaldo, John R.; Young, Howard A.

doi:10.4049/jimmunol.170.4.1763

Cited by 58 publications

(48 citation statements)

References 33 publications

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“…This balance is influenced by several factors such as the induction of activating ligands [11], the down-modulation of target cell MHC class I [34], cytokines [35], and also by the modulation of activating receptors as described here. The down-modulation of 2B4 is dependent on the engagement of the receptor, either by antibodies or by its ligand.…”

Section: Discussionmentioning

confidence: 99%

Regulation of 2B4 (CD244)‐mediated NK cell activation by ligand‐induced receptor modulation

2006

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Natural killer (NK) cell activity can be stimulated by different surface receptors. 2B4 is a member of the signaling lymphocyte activation molecule (SLAM)-related receptor family and is important for stimulating human NK cell cytotoxicity and cytokine production. Here we show that stimulation of human NK cells by antibody-mediated 2B4 cross-linking or incubation with target cells expressing the 2B4 ligand CD48 results in a strong down-modulation of 2B4 surface expression. This down-modulation is observed in NK cell lines, purified human NK cells and NK cell clones, and is accompanied by an internalization of 2B4. The modulation of 2B4 is dependent on the activity of Src-family kinases, but independent of PI3 K activity or actin polymerization. Inhibitory receptors can interfere with 2B4-mediated signals and NK cell activation. However, co-engagement of inhibitory killer cell Ig-like receptors has no influence on the down-modulation of 2B4. This suggests that the modulation of 2B4 expression is independent of inhibitory receptors. The lower surface expression of 2B4 after ligandinduced down-modulation results in reduced 2B4-mediated NK cell activation and cytotoxicity. The modulation of activating surface receptors may therefore be another mechanism for the fine-tuning of NK cell activity and may lead to the adaptation of NK cell cytotoxicity in tissues with high ligand expression. IntroductionNatural killer (NK) cells have the ability to immediately kill infected or transformed cells and are important for the control of acute viral infections [1,2]. By modulating dendritic cell functions, NK cells also play an important role in the development of protective T cell responses against intracellular pathogens and tumors [3,4]. The activity of NK cells is regulated by a balance of positive and negative signals, mediated by different surface receptors [5,6]. Human NK cell inhibitory receptors include members of the killer cell Ig-like receptors (KIR), and the CD94/NKG2A heterodimer, which recognize MHC class I molecules on target cells [7]. NK cell activation can be mediated by a variety of different receptors, which include the natural cytotoxicity receptors (NCR) NKp30, NKp44, NKp46, the activating receptors NKG2D and DNAM-1, and members of the signaling lymphocyte activation molecule (SLAM)-related receptors (SRR) 2B4 (CD244), NTB-A and CRACC (CS1, CD319) [6,8,9].Under physiological conditions the positive and negative signals are balanced, ensuring that NK cells do not attack normal cells [10]. Loss of MHC class I expression on infected or transformed cells can reduce the negative signal mediated by inhibitory NK cell receptors, thereby tilting the balance toward activation, resulting in NK cell-mediated lysis. Alternatively, upregulation of ligands for the activating NKG2D receptor can enhance the positive signal, resulting in the lysis of target cells with normal MHC class I expression [11]. The activity of NK cells is not only dictated by the expression of stimulating or inhibiting ligands on target cells. The ...

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Section: Discussionmentioning

confidence: 99%

Regulation of 2B4 (CD244)‐mediated NK cell activation by ligand‐induced receptor modulation

2006

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“…NK cells also produce a variety of cytokines, including IFNγ, TNF and granulocyte/macrophage colony-stimulating factor (GM-CSF) [69][70][71] . NK-cell target recognition and killing activity rely on the expression of a set of so-called inhibitory receptors (such as members of the Ly49 and CD94 families) and activating receptors (such as NK1.1, DX5 and CD69), which recognize ligands on target cells [72][73][74] .…”

Section: Tam Control Of Natural-killer-cell Differentiationmentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

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Recent studies have revealed that the TAM receptor protein tyrosine kinases -TYRO3, AXL and MER -have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.Receptor protein tyrosine kinases (PTKs) are cell-surface transmembrane receptors that contain a regulated PTK activity within their cytoplasmic domains. They function as sensors for extracellular ligands, the binding of which triggers receptor dimerization and activation of the receptor's kinase. This leads to the recruitment, phosphorylation and activation of multiple downstream signalling proteins, which ultimately change the physiology of cells. Although there are only 58 receptor PTK genes in the human genome 1 (see the human kinome website), the signal transduction cascades initiated by receptor PTK activation control diverse cellular processes -from cell differentiation to cell death. Well-known receptor PTK subfamilies include the ERBB receptors, which have essential roles in cardiac and neural development and the progression of some forms of breast cancer 2 ; and the ephrin receptors, which are required for tissue morphogenesis and the patterning of neuronal connections in the developing brain 3 .The focus of this Review, the TAM group, was among the last receptor PTK subfamilies to be identified, and the biological roles of its three members -TYRO3, AXL and MERremained uncharacterized for several years. Largely through the analysis of engineered lossof-function mutants in mice, these roles have become increasingly apparent. They reflect a specific requirement for TAM signalling in settings in which fully differentiated cells, tissues and organs must be maintained in the face of continuous challenge, turnover and renewal. In humans, ongoing homeostatic regulation of this sort must be carried out, frequently on a daily basis, for decades. Although an essential role for TAM regulation of tissue homeostasis is evident in the adult nervous, reproductive and vascular systems, it is in In this Review, we highlight the central roles that TAM signalling has in the intrinsic inhibition of the inflammatory response to pathogens by dendritic cells (DCs) and macrophages; during phagocytosis of apoptotic cells by these same cells; and in the maturation and killing activity of natural killer (NK) cells. We also discuss how, in many or all of these settings, TAM receptors depend on and interact with cytokine receptors. TAM receptors and ligandsThe three TAM receptors, TYRO3, AXL and MER, were identified as a distinct receptor PTK subfamily in 1991 (REFS 4,5 ). Subsequent cloning of full-length cDNAs by multiple labo...

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“…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.…”

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confidence: 99%

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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Expression of IFN-γ Upon Triggering of Activating Ly49D NK Receptors In Vitro and In Vivo: Costimulation with IL-12 or IL-18 Overrides Inhibitory Receptors

Cited by 58 publications

References 33 publications

Regulation of 2B4 (CD244)‐mediated NK cell activation by ligand‐induced receptor modulation

Regulation of 2B4 (CD244)‐mediated NK cell activation by ligand‐induced receptor modulation

Immunobiology of the TAM receptors

Continuous CD27 triggering in vivo strongly reduces NK cell numbers

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