Temporal regulation of natural killer T cell interferon gamma responses by β-catenin-dependent and -independent Wnt signaling

Kling, Jessica C., Jordan, Margaret A., Pitt, Lauren A., Meiners, Jana, Thanh-Tran, Thao, Son Tran, Le, Nguyen, T.K., Mittal, Deepak, Villani, Rehan, Steptoe, Raymond J., Khosrotehrani, Kiarash, Berzins, Stuart P., Baxter, Alan G., Godfrey, Dale I., Blumenthal, Antje, and UNSPECIFIED (2018) Temporal regulation of natural killer T cell interferon gamma responses by β-catenin-dependent and -independent Wnt signaling. Frontiers in Immunology, 9. 483.

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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.

Item ID: 52927
Item Type: Article (Research - C1)
ISSN: 1664-3224
Keywords: NKT cells, Wnt signalling
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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Funders: University of Queensland (UQ), University of Queensland Diamantina Institute, National Health and Medical Research Council (NHMRC), MS Research Australia, International Balzan Foundation (IBF)
Projects and Grants: UQ Early Career Researcher Grant, NHMRC project 1013667, NHMRC project 1113293, UQ Postdoctoral Research Fellowship, NHMRC Betty Cuthbert Fellowship, NHMRC Research Fellowship, IBF Research Fellowship
Date Deposited: 21 Mar 2018 02:32
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320406 Immunogenetics (incl. genetic immunology) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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