Suppressor of Cytokine Signaling 2 Regulates IL-15–Primed Human NK Cell Function via Control of Phosphorylated Pyk2
Open Access
- 15 July 2010
- journal article
- Published by The American Association of Immunologists
- Vol. 185 (2), 917-928
- https://doi.org/10.4049/jimmunol.1000784
Abstract
NK cells are capable of killing virus-infected or tumor cells and producing IFN-γ. Resting NK cells, however, have only minimal cytolytic activity and secrete a low level of IFN-γ. The cytokine IL-15 can promote the expression of effector functions by resting NK cells. In this study, we demonstrate that suppressor of cytokine signaling 2 (SOCS2) has a novel role in IL-15–primed human NK cell function. SOCS2 expression was upregulated in NK cells following stimulation with IL-15. During IL-15–mediated NK cell priming, SOCS2 interacted with phosphorylated proline-rich tyrosine kinase 2 (Pyk2) at tyrosine 402 (p-Pyk2Tyr402) and induced the proteasome-mediated degradation of p-Pyk2Tyr402 via ubiquitination. Knockdown of SOCS2 resulted in the accumulation of p-Pyk2Tyr402 and blocked NK cell effector functions. In addition, NK cell cytolytic activity and IFN-γ production were inhibited by overexpression of the wild-type of Pyk2 but not by the overexpression of tyrosine 402 mutant of Pyk2. These results suggest that SOCS2 regulates human NK cell effector functions via control of phosphorylated Pyk2 depending on IL-15 existence.Keywords
This publication has 44 references indexed in Scilit:
- Native and aspirin-triggered lipoxins control innate immunity by inducing proteasomal degradation of TRAF6The Journal of Experimental Medicine, 2008
- JNK MAP kinase activation is required for MTOC and granule polarization in NKG2D-mediated NK cell cytotoxicityProceedings of the National Academy of Sciences, 2008
- Interleukin 15–mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1Nature Immunology, 2007
- Dendritic Cells Prime Natural Killer Cells by trans-Presenting Interleukin 15Immunity, 2007
- The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine designNature Reviews Immunology, 2006
- CD28-stimulated ERK2 phosphorylation is required for polarization of the microtubule organizing center and granules in YTS NK cellsProceedings of the National Academy of Sciences, 2006
- Dysregulation of signaling pathways in CD45-deficient NK cells leads to differentially regulated cytotoxicity and cytokine productionProceedings of the National Academy of Sciences, 2006
- Stage-dependent gene expression profiles during natural killer cell developmentGenomics, 2005
- Lymphocide: cytokines and the control of lymphoid homeostasisNature Reviews Immunology, 2002
- Natural killer cells, viruses and cancerNature Reviews Immunology, 2001