Abstract
Activating and inhibitory receptors control natural killer (NK) cell activity. T-cell immunoglobulin and ITIM (immunoreceptor tyrosine-based inhibition motif) domain (TIGIT) was recently identified as a new inhibitory receptor on T and NK cells that suppressed their effector functions. TIGIT harbors the immunoreceptor tail tyrosine (ITT)-like and ITIM motifs in its cytoplasmic tail. However, how its ITT-like motif functions in TIGIT-mediated negative signaling is still unclear. Here, we show that TIGIT/PVR (poliovirus receptor) engagement disrupts granule polarization leading to loss of killing activity of NK cells. The ITT-like motif of TIGIT has a major role in its negative signaling. After TIGIT/PVR ligation, the ITT-like motif is phosphorylated at Tyr225 and binds to cytosolic adapter Grb2, which can recruit SHIP1 to prematurely terminate phosphatidylinositol 3-kinase (PI3K) and MAPK signaling, leading to downregulation of NK cell function. In support of this, Tyr225 or Asn227 mutation leads to restoration of TIGIT/PVR-mediated cytotoxicity, and SHIP1 silencing can dramatically abolish TIGIT/PVR-mediated killing inhibition.
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Abbreviations
- NK:
-
natural killer
- TIGIT:
-
T-cell immunoglobulin and ITIM domain
- PVR:
-
poliovirus receptor
- ITT:
-
immunoreceptor tail tyrosine
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Acknowledgements
We thank Drs. André Veillette and Geng Zhang for critical discussion; Dr. Byung-Chul Oh for providing plasmids; Dr. Jane L Grogan for providing some antibodies. We also thank Junying Jia, Chunchun Liu and Yan Teng for technical assistance and Shuo Wang, Li Wang, Chao Zhong and Pengyan Xia for helpful discussions. This work was supported by the National Natural Science Foundation of China (30830030, 31170837, 30972676), the grants from the Ministry of Science and Technology China (2010CB911902) and from the Chinese Academy of Sciences (XDA01010407).
Author contributions
SL and HZ designed and performed research, analyzed data and wrote the manuscript; ML, DH and CL performed some experiments; BG and BJ provided vectors and cell lines and analyzed the data; ZF initiated the research, analyzed the data and wrote the manuscript.
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Liu, S., Zhang, H., Li, M. et al. Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells. Cell Death Differ 20, 456–464 (2013). https://doi.org/10.1038/cdd.2012.141
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DOI: https://doi.org/10.1038/cdd.2012.141
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