Temporal regulation of natural killer T cell interferon gamma responses by β-catenin-dependent and-independent wnt signaling
| Autor: | Jessica C. Kling, Margaret A. Jordan, Lauren A. Pitt, Jana Meiners, Thao Thanh-Tran, Le Son Tran, Tam T. K. Nguyen, Deepak Mittal, Rehan Villani, Raymond J. Steptoe, Kiarash Khosrotehrani, Stuart P. Berzins, Alan G. Baxter, Dale I. Godfrey, Antje Blumenthal |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
lcsh:Immunologic diseases. Allergy Beta-catenin Immunology Medizin Pyrimidinones Biology Receptors G-Protein-Coupled Interferon-gamma Mice 03 medical and health sciences Wnt medicine Animals Immunology and Allergy Interferon gamma Benzothiazoles Wnt Signaling Pathway beta Catenin Interleukin 4 Original Research α-galactosylceramide Effector Intracellular Signaling Peptides and Proteins Wnt signaling pathway IL-4 β-catenin Bridged Bicyclo Compounds Heterocyclic Natural killer T cell 3. Good health Cell biology natural killer T cell 030104 developmental biology interferon gamma IL-12 Catenin Interleukin 12 biology.protein Natural Killer T-Cells Female Interleukin-4 lcsh:RC581-607 medicine.drug |
| Zdroj: | Frontiers in Immunology, Vol 9 (2018) Frontiers in Immunology |
| Popis: | 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. CA extern |
| Databáze: | OpenAIRE |
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