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

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 5

In vivo IL-2 administration enhances NK cell cytotoxicity and F-actin content in a WAS patient ex vivo.

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In vivo IL-2 administration enhances NK cell cytotoxicity and F-actin co...
A patient with grade 2 WAS was enrolled and treated with subcutaneous IL-2 using 0.5 × 106 U/m2/d × 5 d for each of 3 treatments as listed (A). Blood was drawn immediately prior to each treatment cycle as well as at the time points specified. (B) Examples of the local reactions noted at the IL-2 injection site. (C) NK cell cytotoxicity using patient PBMCs (dashed line) in 51Cr-release assay against K562 target cells from the initial screen (week –1) and the penultimate blood draw (week 23) compared with PBMC of an individual healthy donor (not treated with IL-2, solid line). (D) F-actin content in patient CD56dim (solid line) and CD56bright (dashed line) NK cells expressed as the MFI percentage of that identified in control over the course of the treatment protocol. The red and orange lines represent the CD56dim and CD56bright pretreatment values, respectively, and the open rectangles correspond to the 5-day periods of IL-2 administration.