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IL-2 induces a WAVE2-dependent pathway for actin reorganization that enables WASp-independent human NK cell function
Jordan S. Orange, … , Pinaki P. Banerjee, Rahul Pandey
Jordan S. Orange, … , Pinaki P. Banerjee, Rahul Pandey
Published March 7, 2011
Citation Information: J Clin Invest. 2011;121(4):1535-1548. https://doi.org/10.1172/JCI44862.
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Research Article Immunology

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

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Abstract

Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency associated with an increased susceptibility to herpesvirus infection and hematologic malignancy as well as a deficiency of NK cell function. It is caused by defective WAS protein (WASp). WASp facilitates filamentous actin (F-actin) branching and is required for F-actin accumulation at the NK cell immunological synapse and NK cell cytotoxicity ex vivo. Importantly, the function of WASp-deficient NK cells can be restored in vitro after exposure to IL-2, but the mechanisms underlying this remain unknown. Using a WASp inhibitor as well as cells from patients with WAS, we have defined a direct effect of IL-2 signaling upon F-actin that is independent of WASp function. We found that IL-2 treatment of a patient with WAS enhanced the cytotoxicity of their NK cells and the F-actin content at the immunological synapses formed by their NK cells. IL-2 stimulation of NK cells in vitro activated the WASp homolog WAVE2, which was required for inducing WASp-independent NK cell function, but not for baseline activity. Thus, WAVE2 and WASp define parallel pathways to F-actin reorganization and function in human NK cells; although WAVE2 was not required for NK cell innate function, it was accessible through adaptive immunity via IL-2. These results demonstrate how overlapping cytoskeletal activities can utilize immunologically distinct pathways to achieve synonymous immune function.

Authors

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

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Figure 1

IL-2 promotes intracellular F-actin content in NK cells.

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IL-2 promotes intracellular F-actin content in NK cells.
(A) YTS, NK92, ...
(A) YTS, NK92, PBMC, or ex vivo NK cells were treated with 125 U/ml of IL-2 for 30 minutes, fixed, permeabilized, and stained with phalloidin Alexa Fluor 647. Percentage of maximal fluorescence intensity of Alexa Fluor 647 is demonstrated for control (gray) and IL-2–treated (white) cells. In PBMCs, only the CD56+CD3– cells were selected. (B) Phalloidin MFI induced by IL-2 over that in control-treated cells according to time of in vitro IL-2 or vehicle exposure (error bars demonstrate SD; *P < 0.05 compared with control-treated cells). (C) Distribution of actin-GFP in control-treated (top) or IL-2–treated (bottom) YTS GFP-actin cells using real-time confocal microscopy. GFP-actin fluorescence is depicted in green, and DRAQ5 DNA dye (nuclear material) is depicted in red. Time = 0:00 represents the addition of IL-2 or vehicle to the imaging chamber. Scale bar: 5 μm. (D) Calculated change from time = 0:00 in mean area intensity of peripheral GFP-actin over the first 8 minutes in control-treated cells (gray triangles) compared with IL-2–treated cells (black squares). Each point represents the mean ± SD from 10 cells, and the IL-2 and control data sets are significantly different (P = 0.0023) via a 2-tailed Mann-Whitney U test. (E) Insoluble F-actin–rich cell fractions prepared from unstimulated, 10-minute, or 120-minute IL-2–stimulated YTS GFP-actin cells were evaluated by Western blot analysis for GFP-actin (top), endogenous actin (middle), and histone H1 (bottom). The numbers beneath the blots provide the densitometric ratio of the GFP or actin signal to that present in the unstimulated lane and are representative of 2 repeats.

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