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Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells.

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.

SUBMITTER: Liu S

PROVIDER: S-EPMC3569986 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells.

Liu S S Zhang H H Li M M Hu D D Li C C Ge B B Jin B B Fan Z Z

Cell death and differentiation 20121116 3

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 tha ...[more]

PMID: 23154388

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Project description:The latent human immunodeficiency virus (HIV) reservoir presents the biggest obstacle to curing HIV chronic infection. Consequently, finding novel strategies to control the HIV reservoir is critical. Natural killer (NK) cells are essential for antiviral immunity. However, the influence of NK cell subsets and their associated inhibitory or activating receptors on their cytotoxicity toward the HIV reservoir has not been fully studied. We investigated the relationship between the percentage of NK cells or NK cell subsets and the HIV reservoir. Our results indicated that the percentage of CD56-CD16+ NK cells was positively associated with HIV reservoir size (i.e., HIV DNA, HIV msRNA, or HIV usRNA). Additionally, we observed that the percentage of IFN-γ+ NK cells was inversely related to the HIV reservoir. Furthermore, the expression of TIGIT on NK cells, particularly CD56-CD16+ and CD56dim NK cell subsets, positively correlated with the HIV reservoir. Notably, individuals with higher percentage of TIGIT+ NK and lower percentage of CD226+ NK cells exhibited larger HIV reservoir. Mechanistically, we discovered that TIGIT could inhibit the PI3K-Akt-mTOR-mTORC1 (s6k) signaling pathway to decrease the production of IFN-γ in NK cells. Importantly, inhibiting TIGIT in NK cells enhanced their ability to eliminate reactivated latently infected CD4+ T cells. Our experiments underscored the crucial role of NK cells in controlling the HIV reservoir and suggested that TIGIT serves as a promising target for enhancing the NK cell-mediated clearance of the HIV reservoir.ImportanceAs a major barrier to human immunodeficiency virus (HIV) cure, HIV reservoir persist in viremia-suppressed infected individuals. NK cells are important antiviral cells, and their impact on reservoir has rarely been reported. We analyzed the relationship between the size of reservoir and NK cell subsets, inhibitory receptor TIGIT expression. Our analysis found that the percentage of CD56-CD16+ NK cells was positively associated with HIV reservoir size. Furthermore, TIGIT expression on NK cells and CD56-CD16+ NK cells or CD56dim NK cells has a positive correlation with the HIV reservoir. TIGIT can inhibit the PI3K-Akt-mTOR-mTORC1 (s6k) signaling pathway to decrease the production of IFN-γ on NK cells. Blocking TIGIT in NK cells can enhance their ability to eliminate reactivated latently infected CD4+ T cells. Our study indicated that NK cells are critical to the control of the reservoir size, and TIGIT may be a target for enhancing the NK cell-mediated elimination of the reservoir.

Dataset Information

Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells.

Publications

Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells.

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