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Antigen-independent adhesion and cell spreading by inducible costimulator engagement inhibits T cell migration in a PI-3K-dependent manner.

ABSTRACT: Engagement of the costimulatory protein ICOS activates effector/memory T cells in tissue by enhancing TCR-mediated proliferation and cytokine production. We now report that in an antigen-independent manner, ICOS also induces adhesion and spreading in human effector/memory T cells, consequently inhibiting cell migration. T cell spreading and elongation after ICOS ligation are accompanied by the formation of two types of actin-rich membrane protrusions: thin, finger-like structures similar to filopodia and short, discrete microspikes. Although filopodia/microspike formation occurs independently of the PI-3K signaling cascade, ICOS-mediated T cell elongation depends on PI-3K activity, which inhibits the accumulation of GTP-bound RhoA. Further inhibition of RhoA activation exacerbates the ICOS-mediated, elongated phenotype. We propose that in inflamed tissue, ICOS engagement by ICOS ligand on a professional or nonprofessional APC prevents the forward motility of the T cell by inhibiting RhoA-dependent uropod retraction. The resulting ICOS-induced T cell spreading and filopodia/microspike formation may promote antigen recognition by enhancing a T cell's scanning potential of an adherent APC surface.

SUBMITTER: Franko JL

PROVIDER: S-EPMC2653947 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The liver capacity to recover from acute liver injury is a critical factor in the development of acute liver failure (ALF) caused by viral infections, ischemia/reperfusion or drug toxicity. Liver healing requires the switching of pro-inflammatory monocyte-derived macrophages(MoMFs) to a reparative phenotype. However, the mechanisms involved are still incompletely characterized. In this study we investigated the contribution of T-lymphocyte/macrophage interaction through the co-stimulatory molecule Inducible T-cell co-stimulator (ICOS; CD278) and its ligand (ICOSL; CD275) in modulating liver repair. The role of ICOS/ICOSL dyad was investigated during the recovery from acute liver damage induced by a single dose of carbon tetrachloride (CCl4). Flow cytometry of non-parenchymal liver cells obtained from CCl4-treated wild-type mice revealed that the recovery from acute liver injury associated with a specific up-regulation of ICOS in CD8+ T-lymphocytes and with an increase in ICOSL expression involving CD11bhigh/F4-80+ hepatic MoMFs. Although ICOS deficiency did not influence the severity of liver damage and the evolution of inflammation, CCl4-treated ICOS knockout (ICOS-/- ) mice showed delayed clearance of liver necrosis and increased mortality. These animals were also characterized by a significant reduction of hepatic reparative MoMFs due to an increased rate of cell apoptosis. An impaired liver healing and loss of reparative MoMFs was similarly evident in ICOSL-deficient mice or following CD8+ T-cells ablation in wild-type mice. The loss of reparative MoMFs was prevented by supplementing CCl4-treated ICOS-/- mice with recombinant ICOS (ICOS-Fc) which also stimulated full recovery from liver injury. These data demonstrated that CD8+ T-lymphocytes play a key role in supporting the survival of reparative MoMFs during liver healing trough ICOS/ICOSL-mediated signaling. These observations open the possibility of targeting ICOS/ICOSL dyad as a novel tool for promoting efficient healing following acute liver injury.

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Antigen-independent adhesion and cell spreading by inducible costimulator engagement inhibits T cell migration in a PI-3K-dependent manner.

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