IL-2 induces a WAVE2-dependent pathway for actin reorganization that enables WASp-independent human NK cell function
Open Access
- 1 April 2011
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 121 (4), 1535-1548
- https://doi.org/10.1172/jci44862
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.Keywords
This publication has 49 references indexed in Scilit:
- Quantitative measurement of F-actin accumulation at the NK cell immunological synapseJournal of Immunological Methods, 2010
- Activation of the WAVE Complex by Coincident Signals Controls Actin AssemblyMolecular Cell, 2009
- Myosin IIA Associates with NK Cell Lytic Granules to Enable Their Interaction with F-Actin and Function at the Immunological SynapsePublished by The American Association of Immunologists ,2009
- The WAVE2 complex regulates T cell receptor signaling to integrins via Abl- and CrkL–C3G-mediated activation of Rap1The Journal of cell biology, 2008
- Formation and function of the lytic NK-cell immunological synapseNature Reviews Immunology, 2008
- The c-Abl tyrosine kinase regulates actin remodeling at the immune synapseBlood, 2008
- Phosphorylation of WAVE2 by MAP kinases regulates persistent cell migration and polarityJournal of Cell Science, 2007
- Cdc42-interacting protein–4 functionally links actin and microtubule networks at the cytolytic NK cell immunological synapseThe Journal of Experimental Medicine, 2007
- WAVE2 Regulates High-Affinity Integrin Binding by Recruiting Vinculin and Talin to the Immunological SynapseMolecular and Cellular Biology, 2007
- A multiinstitutional survey of the Wiskott-Aldrich syndromeThe Journal of Pediatrics, 1994