Temporal Regulation of Natural Killer T Cell Interferon Gamma Responses by ?-Catenin-Dependent and -Independent Wnt Signaling.

ABSTRACT: Natural killer T (NKT) cells are prominent innate-like lymphocytes in the liver with critical roles in immune responses during infection, cancer, and autoimmunity. Interferon gamma (IFN-?) and IL-4 are key cytokines rapidly produced by NKT cells upon recognition of glycolipid antigens presented by antigen-presenting cells (APCs). It has previously been reported that the transcriptional coactivator ?-catenin regulates NKT cell differentiation and functionally biases NKT cell responses toward IL-4, at the expense of IFN-? production. ?-Catenin is not only a central effector of Wnt signaling but also contributes to other signaling networks. It is currently unknown whether Wnt ligands regulate NKT cell functions. We thus investigated how Wnt ligands and ?-catenin activity shape liver NKT cell functions in vivo in response to the glycolipid antigen, ?-galactosylceramide (?-GalCer) using a mouse model. Pharmacologic targeting of ?-catenin activity with ICG001, as well as myeloid-specific genetic ablation of Wntless (Wls), to specifically target Wnt protein release by APCs, enhanced early IFN-? responses. By contrast, within several hours of ?-GalCer challenge, myeloid-specific Wls deficiency, as well as pharmacologic targeting of Wnt release using the small molecule inhibitor IWP-2 impaired ?-GalCer-induced IFN-? responses, independent of ?-catenin activity. These data suggest that myeloid cell-derived Wnt ligands drive early Wnt/?-catenin signaling that curbs IFN-? responses, but that, subsequently, Wnt ligands sustain IFN-? expression independent of ?-catenin activity. Our analyses in ICG001-treated mice confirmed a role for ?-catenin activity in driving early IL-4 responses by liver NKT cells. However, neither pharmacologic nor genetic perturbation of Wnt production affected the IL-4 response, suggesting that IL-4 production by NKT cells in response to ?-GalCer is not driven by released Wnt ligands. Collectively, these data reveal complex temporal roles of Wnt ligands and ?-catenin signaling in the regulation of liver NKT cell activation, and highlight Wnt-dependent and -independent contributions of ?-catenin to NKT cell functions.

SUBMITTER: Kling JC 

PROVIDER: S-EPMC5864864 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature