title: T-cell immunoglobulin and ITIM domain (TIGIT) receptor/poliovirus receptor (PVR) ligand engagement suppresses interferon-γ production of natural killer cells via β-arrestin 2-mediated negative signaling.
abstract: Natural killer (NK) cell activation is well orchestrated by a wide array of NK cell receptor repertoire. T-cell immunoglobulin and ITIM domain (TIGIT) receptor was recently defined as an inhibitory receptor that is expressed on NK cells and T cells. TIGIT receptor/poliovirus 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 knock-out NK cells produce much more IFN-γ. TIGIT/PVR ligation signaling mediates suppression of IFN-γ production via the 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.
authors.affiliation: From the CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, University of Chinese Academy of Sciences, Beijing 100049.
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.affiliation: From the CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, University of Chinese Academy of Sciences, Beijing 100049.
authors.forename: Pengyan
authors.initials: P
authors.lastname: Xia
authors.affiliation: From the CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101.
authors.forename: Ying
authors.initials: Y
authors.lastname: Du
authors.affiliation: From the CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, University of Chinese Academy of Sciences, Beijing 100049.
authors.forename: Shengwu
authors.initials: S
authors.lastname: Liu
authors.affiliation: From the CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, University of Chinese Academy of Sciences, Beijing 100049.
authors.forename: Guanling
authors.initials: G
authors.lastname: Huang
authors.affiliation: From the CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, University of Chinese Academy of Sciences, Beijing 100049.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: From the CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101.
authors.forename: Honglian
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Proteomics, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing 100071, and.
authors.forename: Ning
authors.initials: N
authors.lastname: Hou
authors.affiliation: State Key Laboratory of Proteomics, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing 100071, and.
authors.forename: Xuan
authors.initials: X
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Luyu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Peifeng
authors.initials: P
authors.lastname: Li
authors.affiliation: State Key Laboratory of Proteomics, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing 100071, and yangx@bmi.ac.cn.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.affiliation: From the CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, fanz@moon.ibp.ac.cn.
authors.forename: Zusen
authors.initials: Z
authors.lastname: Fan
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D007152:Immunologic Capping / Q000502:physiology; D000072181:Inositol Polyphosphate 5-Phosphatases; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; C000605258:Arrb2 protein, mouse; D019390:Arrestins; C573415:IFNG protein, human; D011971:Receptors, Immunologic; D011991:Receptors, Virus; C556305:T cell Ig and ITIM domain protein, mouse; C534712:TIGIT protein, human; D048029:TNF Receptor-Associated Factor 6; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; C066100:poliovirus receptor; D007371:Interferon-gamma; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
keywords: Immunology; Innate Immunity; Interferon; Natural Killer Cells (NK Cells); Signaling