Temporal regulation of natural Killer T cell interferon gamma responses by beta-catenin-Dependent and -Independent Wnt signaling
AuthorKling, JC; Jordan, MA; Pitt, LA; Meiners, J; Thao, T-T; Le, ST; Nguyen, TTK; Mittal, D; Villani, R; Steptoe, RJ; ...
Source TitleFrontiers in Immunology
PublisherFRONTIERS MEDIA SA
AffiliationMicrobiology and Immunology
Document TypeJournal Article
CitationsKling, J. C., Jordan, M. A., Pitt, L. A., Meiners, J., Thao, T. -T., Le, S. T., Nguyen, T. T. K., Mittal, D., Villani, R., Steptoe, R. J., Khosrotehrani, K., Berzins, S. P., Baxter, A. G., Godfrey, D. I. & Blumenthal, A. (2018). Temporal regulation of natural Killer T cell interferon gamma responses by beta-catenin-Dependent and -Independent Wnt signaling. FRONTIERS IN IMMUNOLOGY, 9 (MAR), https://doi.org/10.3389/fimmu.2018.00483.
Access StatusOpen Access
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.
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