T-cell Immunoglobulin and ITIM Domain (TIGIT) Receptor/Poliovirus Receptor (PVR) Ligand Engagement Suppresses Interferon-{gamma} Production of Natural Killer Cells via {beta}-arrestin 2-mediated Negative Signaling [Cell Biology]

May 9th, 2014 by Li, M., Xia, P., Du, Y., Liu, S., Huang, G., Chen, J., Zhang, H., Hou, N., Cheng, X., Zhou, L., Li, P., Yang, X., Fan, Z.

Natural killer (NK) cell activation is well orchestrated by a wide array of NK cell receptor repertoire. TIGIT receptor was recently defined as an inhibitory receptor that is expressed on NK cells and T cells. TIGIT receptor/PVR ligand engagement signaling inhibits cytotoxicity mediated by NK and CD8+ T cells. However, it is unclear how TIGIT/PVR signaling regulates cytokine secretion in NK cells. Here we show that TIGIT/PVR engagement suppresses interferon-γ(IFN-γ) production of NK cells. TIGIT transgenic NK cells generate less IFN-γ undergoing TIGIT/PVR ligation. Moreover, TIGIT knockout NK cells produce much more IFN-γ. TIGIT/PVR ligation signaling mediates suppression of IFN-γ production via NF-κB pathway. We identified a novel adaptor β-arrestin 2 that associates with phosphorylated TIGIT for further recruitment of SHIP1 (SH2-containing inositol phosphatase 1) through the ITT-like motif. Importantly, SHIP1, but not other phosphatases, impairs the TNF receptor associated factor 6 (TRAF6) autoubiquitination to abolish NF-κB activation, leading to suppression of IFN-γ production in NK cells.
  • Posted in Journal of Biological Chemistry, Publications
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