TY  - JOUR
AU  - Kling, JC
AU  - Jordan, MA
AU  - Pitt, LA
AU  - Meiners, J
AU  - Thao, T-T
AU  - Le, ST
AU  - Nguyen, TTK
AU  - Mittal, D
AU  - Villani, R
AU  - Steptoe, RJ
AU  - Khosrotehrani, K
AU  - Berzins, SP
AU  - Baxter, AG
AU  - Godfrey, DI
AU  - Blumenthal, A
Y2  - 2020/12/17
Y1  - 2018/03/16
SN  - 1664-3224
UR  - http://hdl.handle.net/11343/254733
AB  - 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.
LA  - English
PB  - FRONTIERS MEDIA SA
T1  - Temporal regulation of natural Killer T cell interferon gamma responses by beta-catenin-Dependent and -Independent Wnt signaling
DO  - 10.3389/fimmu.2018.00483
IS  - Frontiers in Immunology
VL  - 9
IS  - MAR
L1  - /bitstream/handle/11343/254733/PMC5864864.pdf?sequence=1&isAllowed=y
ER  -