Impaired natural and CD16-mediated NK cell cytotoxicity in patients with WAS and XLT: ability of IL-2 to correct NK cell functional defect

Gismondi, Angela; Cifaldi, Loredana; Mazza, Cinzia; Giliani, Silvia; Parolini, Silvia; Morrone, Stefania; Jacobelli, Jordan; Bandiera, Elisabetta; Notarangelo, Luigi D.; Santoni, Angela

doi:10.1182/blood-2003-07-2621

Cited by 129 publications

(141 citation statements)

References 37 publications

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“…LFA-1 engagement on NK cells induces phosphorylation of the Wiskott-Aldrich syndrome protein, a known regulator of the actin cytoskeleton (36). Our data are in line with the important role of the actin cytoskeleton for LFA-1-mediated adhesion, as inhibition of actin polymerization greatly reduced the adhesion to HeLa-CD48.…”

Section: Discussionsupporting

confidence: 85%

2B4 Engagement Mediates Rapid LFA-1 and Actin-Dependent NK Cell Adhesion to Tumor Cells as Measured by Single Cell Force Spectroscopy

Hoffmann

Cohnen

Ludwig

et al. 2011

The Journal of Immunology

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Adhesion to tumor target cells is essential for initiation and execution of cellular cytotoxicity. In this study, we use single cell force spectroscopy to determine the exact biophysical values of the interaction forces between NK cells and tumor cells. We show that engagement of the activating NK cell receptor 2B4 can rapidly mediate an increase in the force necessary to separate NK cells from tumor cells, starting from 1 nN and increasing to 3 nN after only 120 s tumor cell contact. This early adhesion was mediated by the integrin LFA-1 and dependent on the actin cytoskeleton. The ability of NK cells to rapidly adhere to tumor target cells is consistent with their function in innate immune responses. Our data further suggest that a killing decision is already made within 120– 300 s of tumor cell contact, supporting the essential function of cell adhesion during the early phase of cellular cytotoxicity.

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Section: Discussionsupporting

confidence: 85%

2B4 Engagement Mediates Rapid LFA-1 and Actin-Dependent NK Cell Adhesion to Tumor Cells as Measured by Single Cell Force Spectroscopy

Hoffmann

Cohnen

Ludwig

et al. 2011

The Journal of Immunology

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“…These results indicate that both proteins, N-WASp and WASp, act downstream Cdc42 for the regulation of NK-cell migration in our experimental conditions. However, the possibility of a defective NKG2D-induced response or chemokine-induced inside-out signaling in WASp knocked down cells cannot be ruled out, as this protein is necessary for the IS formation and it has been shown that its function is not compensated by N-WASp in NK cells [27,41].…”

Section: Discussionmentioning

confidence: 99%

Wiskott‐Aldrich syndrome protein (WASp) and N‐WASp are involved in the regulation of NK‐cell migration upon NKG2D activation

2012

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NKG2D is a transmembrane receptor mainly expressed on CD8 + T cells and NK cells. Engagement of NKG2D with its ligands can trigger a cytotoxic response. It has beenshown that tumor cells deliver soluble NKG2D ligands as a mechanism of immune evasion through the downregulation of surface-expressed NKG2D. These ligands may be also secreted in microvesicles and regulate NK-cell function, but the existence of alternative mechanisms has not been explored. In this study, we describe that NKG2D activation inhibits NK-cell chemotaxis toward a CXCL12 gradient. Costimulation of the inhibitory receptor NKG2A rescues NK-cell migration rates. Thus, the balance of NKG2D/NKG2A activation may determine the migratory ability of NK cells. Furthermore, our data indicated that NKG2D cross-linking induces the activation of the Rho GTPases Rac1 and Cdc42, while RhoA activity is decreased. Pharmacological inhibition of the Cdc42 effectors Wiskott-Aldrich syndrome protein (WASp)/N-WASp, and the reduction of their levels using RNA interference partially abolished NKG2D-mediated impairment of cell migration, suggesting a pivotal role of Cdc42 in the regulation of NK-cell migration by NKG2D activation. Therefore, our results provide a new mechanism that may contribute to the immune response or evasion in tumors.Keywords: Chemotaxis r Migration r NKG2D r Rho GTPases r WASp Introduction NK cells are the first host defense against viral infections and tumors. Degranulation and secretion of cytokines and cytotoxic molecules are the main NK-cell functions. The outcome of NKcell activity is regulated by a balance between activating and inhibitory signals delivered by a repertoire of surface receptors. In human NK cells, these receptors may be classified in killer cell immunoglobulin-like receptors (KIR), natural cytotoxic receptors (NCRs), or C-type lectin receptors [1][2][3]. NKG2D is a C-type lectin Correspondence: Dr. Carlos López-Larrea e-mail: inmuno@hca.es activating receptor which is expressed not only in NK cells, acting as an activating receptor itself, but also in γδ T, CD8 + αβ T lymphocytes and NKT cells in humans, where it acts as a costimulatory molecule [4,5].In humans, the ligands for NKG2D (NKG2DL) are major histocompatibility class I-related chain A/B (MICA/B) and UL-16 binding proteins 1-5 (ULBP1-5) [6]. NKG2D surface levels are regulated by these ligands. In fact, NKG2DL expression may result in immune activation or immune evasion. Although ligand expression is normally restricted under physiological conditions, * These authors have equally contributed to this work.www.eji-journal.eu Eur. J. Immunol. 2012. 42: 2142-2151 Leukocyte signaling 2143it is increased in a broad variety of malignant diseases. High expression of MICA and ULBP2 is detected in ovarian cancer tissue and related to a poor prognosis [7]. Expression of NKG2DL on the cell surface of leukemia cells has also been described [8]. Furthermore, it has been described that the soluble forms of NKG2DL may be released from tumor cells [9,10] and that elevated levels a...

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“…54 Finally, the impaired secretion induced by Ca 2ϩ ionophore indicates that the neuronal ␥-and, to a lesser extent, ␣-dependent signals, also control IP3/Ca 2ϩ -independent step(s). One interesting possibility is the PIP2-mediated regulation of Wiskott-Aldrich syndrome protein (WASP)-Arp2/3 pathway, which is required for actin nucleation 55 and for the formation of an organized cytolytic synapse 56,57 ; another possibility is the control of vesicle fusion step via PIP2 interaction with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) factor syntaxin, as reported in other secretory systems. 58 Notably, WASP and syntaxin 11 mutations are responsible for Wiskott-Aldrich syndrome 56,57 and familiar hemophagocytic lymphohistiocytosis 4 immunodeficiencies, 59 respectively, both characterized by a defective cytotoxic function.…”

Section: Org Frommentioning

confidence: 95%

PI5KI-dependent signals are critical regulators of the cytolytic secretory pathway

Micucci

Capuano

Marchetti

et al. 2008

Blood

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Although membrane phospholipid phosphatidylinositol-4,5bisphosphate (PIP2) plays a key role as signaling intermediate and coordinator of actin dynamics and vesicle trafficking, it remains completely unknown its involvement in the activation of cytolytic machinery. By live confocal imaging of primary human natural killer (NK) cells expressing the chimeric protein GFP-PH, we observed, during effector-target cell interaction, the consumption of a preexisting PIP2 pool, which is critically required for the activation of cytolytic machinery. We identified type I phosphatidylinositol-4-phosphate-5-kinase (PI5KI) ␣ and ␥ isoforms as the enzymes responsible for PIP2 synthesis in NK cells. By hRNA-driven gene silencing, we observed that both enzymes are required for the proper activation of NK cytotoxicity and for inositol-1,4,5-trisphosphate (IP3) generation on receptor stimulation. In an attempt to elucidate the specific step controlled by PI5KIs, we found that lytic granule secretion but not polarization resulted in impaired PI5KI␣-and PI5KI␥-silenced cells. Our findings delineate a novel mechanism implicating PI5KI␣ and PI5KI␥ isoforms in the synthesis of PIP2 pools critically required for IP3-dependent Ca 2؉ IntroductionNatural killer (NK) cells and cytotoxic T lymphocytes are critical effectors in the defense against tumor and viral infections 1 ; they exert cytotoxic function through the polarized secretion of granules containing proteolytic molecules, such as perforin and granzymes. This process involves several steps, including the formation of a cytolytic synapse between cytolytic effector and target cell, the rapid reorientation of the microtubule-organizing center along with lytic granules toward the target contact area followed by granule docking and fusion at specialized secretory domains within the cytolytic synapse. 2,3 Several structurally distinct receptors have been implicated in the activation of NK-cell cytolytic machinery: when cross-linked by the corresponding ligands on target cell, they trigger multiple and intersecting signaling pathways responsible for functional activation. 4 A vast array of activating NK receptors belonging to different families are coupled to the lipid modifying enzymes phosphatidylinositol3-kinase (PI3K) and phospholipase C␥ (PLC␥), which provide signals critically required for the activation of the cytolytic machinery [5][6][7][8] ; notably, both enzymes use the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2) as common substrate. 9 Besides its role as signaling intermediate, PIP2 also acts as critical regulator of various cellular processes, including actin remodeling, membrane and vesicle trafficking, adhesion, and ion transport. 10,11 Surprisingly, the role of PIP2 and its regulatory mechanisms in lymphocyte-mediated cytotoxicity remain completely undefined.The main cellular source of PIP2 are type I phosphatidylinositol-4-phosphate-5-kinase (PI5KI) family members which phosphorylate PI4P on the D5 position of the inositol ring. Three major PI5KI is...

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Impaired natural and CD16-mediated NK cell cytotoxicity in patients with WAS and XLT: ability of IL-2 to correct NK cell functional defect

Cited by 129 publications

References 37 publications

2B4 Engagement Mediates Rapid LFA-1 and Actin-Dependent NK Cell Adhesion to Tumor Cells as Measured by Single Cell Force Spectroscopy

2B4 Engagement Mediates Rapid LFA-1 and Actin-Dependent NK Cell Adhesion to Tumor Cells as Measured by Single Cell Force Spectroscopy

Wiskott‐Aldrich syndrome protein (WASp) and N‐WASp are involved in the regulation of NK‐cell migration upon NKG2D activation

PI5KI-dependent signals are critical regulators of the cytolytic secretory pathway

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