Wiskott–Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin to NK cell-activating immunologic synapses

Orange, Jordan S.; Ramesh, Narayanaswamy; Remold‐O′Donnell, Eileen; Sasahara, Yoji; Koopman, Louise A.; Byrne, Michael; Bonilla, Francisco A.; Rosen, Fred S.; Geha, Raif S.; Strominger, Jack L.

doi:10.1073/pnas.162376099

Cited by 268 publications

(296 citation statements)

References 34 publications

Supporting

Mentioning

280

Contrasting

Unclassified

Order By: Relevance

“…5A and B). In human NK cells, WASp is required for cytotoxic activity and the formation of the IS [27]. Under effect of NKG2D activation on cell migration and F-actin content was observed in our knock-down experiments.…”

Section: N-wasp Involvement In Nkg2d-mediated Migrationsupporting

confidence: 57%

“…The major findings of the involvement of their interaction are described in lymphocytes of patients suffering WAS. WASp function is crucial in T-cell chemotaxis [38][39][40] and is required to correctly form the IS in NK cells, as mutations in WASp impaired NK activity [27]. However, implication of N-WASp in NKG2D-mediated signaling and NK-cell motility has not been explored.…”

Section: Discussionmentioning

confidence: 99%

“…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%

“…5A and B). In human NK cells, WASp is required for cytotoxic activity and the formation of the IS [27]. Under control conditions, cells transfected with siRNA for WASp showed a dramatic reduction in CXCL12-induced chemotaxis (*p < 0.05; Fig.…”

Section: N-wasp Involvement In Nkg2d-mediated Migrationmentioning

confidence: 92%

See 3 more Smart Citations

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

2012

View full text Add to dashboard Cite

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...

show abstract

Section: N-wasp Involvement In Nkg2d-mediated Migrationsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: N-wasp Involvement In Nkg2d-mediated Migrationmentioning

confidence: 92%

See 2 more Smart Citations

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

2012

View full text Add to dashboard Cite

show abstract

“…Correspondingly, confocal microscopy of myosin II showed it to be primarily localized to a multiprotein complex formed during activating NKIS formation ( 10 ). This complex contains at least seven proteins, including Wiskott-Aldrich syndrome protein (WASp), which is required for F-actin reorganization at the NKIS ( 11 ).…”

mentioning

confidence: 99%

Myosin IIA is required for cytolytic granule exocytosis in human NK cells

Andzelm¹,

Chen²,

Krzewski³

et al. 2007

J Cell Biol

Self Cite

View full text Add to dashboard Cite

Signal Transduction During Activation and Inhibition of Natural Killer Cells

2010

View full text Add to dashboard Cite

Natural killer (NK) cells are important for early immune responses to viral infections and cancer. Upon activation, NK cells secrete cytokines and chemokines, and kill sensitive target cells by releasing the content of cytolytic granules. This unit is focused on the signal transduction pathways that regulate NK cell activities in response to contact with other cells. We will highlight signals regulating NK cell adhesion to target cells and describe the induction of cellular cytotoxicity by the engagement of different NK cell activation receptors. Negative signaling induced by inhibitory receptors opposes NK cell activation and provides an important safeguard from NK cell reactivity toward normal, healthy cells. We will discuss the complex integration of the different signals that occur during interaction of NK cells with target cells. Curr. Protoc. Immunol. 90:11.9B.1‐11.9B.17. © 2010 by John Wiley & Sons, Inc.

show abstract

Wiskott–Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin to NK cell-activating immunologic synapses

Cited by 268 publications

References 34 publications

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

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

Myosin IIA is required for cytolytic granule exocytosis in human NK cells

Signal Transduction During Activation and Inhibition of Natural Killer Cells

Contact Info

Product

Resources

About