Temporal Regulation of Natural Killer T Cell Interferon Gamma Responses by β-Catenin-Dependent and -Independent Wnt Signaling.
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-γ) 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 β-catenin regulates NKT cell differentiation and functionally biases NKT cell responses toward IL-4, at the expense of IFN-γ production. β-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 β-catenin activity shape liver NKT cell functions in vivo in response to the glycolipid antigen, α-galactosylceramide (α-GalCer) using a mouse model. Pharmacologic targeting of β-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-γ responses. By contrast, within several hours of α-GalCer challenge, myeloid-specific Wls deficiency, as well as pharmacologic targeting of Wnt release using the small molecule inhibitor IWP-2 impaired α-GalCer-induced IFN-γ responses, independent of β-catenin activity. These data suggest that myeloid cell-derived Wnt ligands drive early Wnt/β-catenin signaling that curbs IFN-γ responses, but that, subsequently, Wnt ligands sustain IFN-γ expression independent of β-catenin activity. Our analyses in ICG001-treated mice confirmed a role for β-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 α-GalCer is not driven by released Wnt ligands. Collectively, these data reveal complex temporal roles of Wnt ligands and β-catenin signaling in the regulation of liver NKT cell activation, and highlight Wnt-dependent and -independent contributions of β-catenin to NKT cell functions.
['Kling|Jessica C|JC|', 'Jordan|Margaret A|MA|', 'Pitt|Lauren A|LA|', 'Meiners|Jana|J|', 'Thanh-Tran|Thao|T|', 'Tran|Le Son|LS|', 'Nguyen|Tam T K|TTK|', 'Mittal|Deepak|D|', 'Villani|Rehan|R|', 'Steptoe|Raymond J|RJ|', 'Khosrotehrani|Kiarash|K|', 'Berzins|Stuart P|SP|', 'Baxter|Alan G|AG|', 'Godfrey|Dale I|DI|', 'Blumenthal|Antje|A|']
D000818:Animals D052160:Benzothiazoles D019086:Bridged Bicyclo Compounds, Heterocyclic D005260:Female D007371:Interferon-gamma D015847:Interleukin-4 D047908:Intracellular Signaling Peptides and Proteins D051379:Mice D055611:Natural Killer T-Cells D011744:Pyrimidinones D043562:Receptors, G-Protein-Coupled D060449:Wnt Signaling Pathway D051176:beta Catenin
natural killer T cell interferon gamma Wnt IL-4 β-catenin α-galactosylceramide IL-12