IL-2 induces a WAVE2-dependent pathway for actin reorganization that enables WASp-independent human NK cell function

Orange, Jordan S.; Roy-Ghanta, Sumita; Mace, Emily M.; Maru, Saumya; Rak, Gregory D.; Sanborn, Keri B.; Fasth, Anders; Saltzman, Rushani; Paisley, Allison; Monaco-Shawver, Linda; Banerjee, Pinaki P.; Pandey, Rahul

doi:10.1172/jci44862

Cited by 76 publications

(100 citation statements)

References 45 publications

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“…In the original study, NK cell lines were cultured in Cytotoxicity assays. NK-92, CD16.NK-92, and CD16.L66H.NK-92 cells and PBMCs were used as effectors against 51 Cr-labeled K562, Raji, and mel1106 cells in 4-hour 51 Cr-release assays, and lytic units were calculated as described previously (42). Serum-free assays were performed using target cells that had been preincubated in serum-free medium at room temperature for at least 30 minutes.…”

Section: Discussionmentioning

confidence: 99%

Human immunodeficiency-causing mutation defines CD16 in spontaneous NK cell cytotoxicity

Forbes²,

et al. 2012

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The Fc receptor on NK cells, FcγRIIIA (CD16), has been extensively studied for its role in mediating antibodydependent cellular cytotoxicity (ADCC). A homozygous missense mutation in CD16 (encoding a L66H substitution) is associated with severe herpesvirus infections in rare patients. Here, we identified a new patient with this CD16 mutation and compared the patient's NK cells to those of the originally reported patient. Patients with the L66H mutation had intact ADCC, but deficient spontaneous NK cell cytotoxicity and decreased surface expression of CD2, a coactivation receptor. Mechanistic studies in a human NK cell line, NK-92, demonstrated that CD16 expression correlated with CD2 surface levels and enabled killing of a melanoma cell line typically resistant to CD16-deficient NK-92 cells. An association between CD16 and CD2 was identified biochemically and at the immunological synapse, which elicited CD16 signaling after CD2 engagement. Stable expression of CD16 L66H in NK-92 cells recapitulated the patient phenotype, abrogating association of CD16 with CD2 as well as CD16 signaling after CD2 ligation. Thus, CD16 serves a role in NK cell-mediated spontaneous cytotoxicity through a specific association with CD2 and represents a potential mechanism underlying a human congenital immunodeficiency.

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Section: Discussionmentioning

confidence: 99%

Human immunodeficiency-causing mutation defines CD16 in spontaneous NK cell cytotoxicity

Forbes²,

et al. 2012

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“…IL-2 is a potent NK cell activating factor 17,18,34,35 that may also help to further prime NK cells for cytotoxicity by promoting lytic granule convergence before target cell binding. This was specific to IL-2 and not a feature of simply adding cytokine to the cells, because IL-10, which signals differently from IL-2 and is generally appreciated for inhibitory effects, 33,34 did not promote this function.…”

Section: Discussionmentioning

confidence: 99%

“…ZM449829 potently and selectively inhibits JAK3 and completely blocks IL-2-induced STAT5 phosphorylation in NK cells. 35 If canonical IL-2 signaling is required for IL-2-mediated lytic granule convergence, we would expect ZM449829 pretreatment to block lytic granule convergence. Thus, YTS GFP-tubulin cells were pretreated with ZM449829 and placed into plain glass imaging chambers to which IL-2 was added after 2 to 4 minutes ( Figure 7B; supplemental Video 11).…”

Section: Lytic Granule Convergence Occurs In Nk Cells Forming An Inhimentioning

confidence: 99%

Rapid activation receptor– or IL-2–induced lytic granule convergence in human natural killer cells requires Src, but not downstream signaling

James

Hsu

Dongre

et al. 2013

Blood

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“…NK cells treated with wiskostatin or transfected with N-WASp-specific siRNA showed no significant decrease in F-actin upon NKG2D crosslinking compared with control cells or control siRNA transfected cells, respectively. A recent study describes that IL-2 may promote actin polymerization via the induction of WAVE2 in a WASp-independent manner [42]. WAVE proteins, which are other WASp family members, mediate cytoskeletal effects of active Rac [43].…”

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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IL-2 induces a WAVE2-dependent pathway for actin reorganization that enables WASp-independent human NK cell function

Abstract: Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency associated with an increased susceptibility

Cited by 76 publications

References 45 publications

Human immunodeficiency-causing mutation defines CD16 in spontaneous NK cell cytotoxicity

Human immunodeficiency-causing mutation defines CD16 in spontaneous NK cell cytotoxicity

Rapid activation receptor– or IL-2–induced lytic granule convergence in human natural killer cells requires Src, but not downstream signaling

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

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