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Multiple pathways help NK cells make connections

[caption id="attachment_282" align="alignleft" width="150" caption="NK cell synaptic actin network"]
[/caption] 30,000x magnification ultra-resolution image of the restored NK cell synaptic actin network from Orange et al.

Published March 7, 2011, by Shawn Pyle

Scientific Show Stopper

Related articles

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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