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- W4313384476 abstract "Abstract The metabolic syndrome support atherosclerosis, but the exact mechanisms for accelerated atherogenesis remain unclear. While the pro-inflammatory role of signal transducer and activator of transcription 4 (STAT4) in atherosclerosis and diet-induced insulin resistance (IR) was recently established, an impact of STAT4 on atherogenesis in conditions of IR is not known. To study the role of STAT4 in IR-accelerated atherosclerosis we generated Stat4−/−Ldlr−/− mice that were fed a diabetogenic diet with added cholesterol (DDC). DDC fed Stat4−/− Ldlr−/−mice demonstrated improved glucose tolerance, insulin sensitivity, and a 36% reduction in atherosclerosis compared with Ldlr−/−controls. Interestingly, we detected a reduction in T follicular helper (Tfh) and plasma B cells, but a sharp elevation in CD8+ Tregs in spleens and aortas of Stat4−/−Ldlr−/−versus Ldlr−/−mice. Similarly, STAT4 deficiency supported CD8+ Treg differentiation in vitro. Additionally, Stat4-deficient CD8+Tregs suppressed Tfh and germinal center B cell development upon immunization with KLH indicating an important role for STAT4 in CD8+ Treg functions in vivo. Effects of STAT4 deficiency were not only restricted to T cells, but had a significant impact on macrophage phenotype. Stat4−/−Ldlr−/− macrophages displayed decreased IFNγ and MHC-II expression. Conditioned media from Stat4−/−Ldlr−/−MFs supported CD8+ Treg but not Tfh cell differentiation in TGFβ-dependent manner, suggesting a role for MF-specific STAT4 in Th cell differentiation. These new findings suggest a novel mechanism by which STAT4 supports atherosclerosis in obese, IR Ldlr−/− mice via increases in MF activation, and modulation of the Tfh/ CD8+ Treg axis systemically and within the aorta." @default.
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- W4313384476 date "2017-05-01" @default.
- W4313384476 modified "2023-09-27" @default.
- W4313384476 title "STAT4 regulates CD8+Treg/Tfh cell axis and promotes atherogenesis in insulin-resistant <i>Ldlr</i>−/− mice" @default.
- W4313384476 doi "https://doi.org/10.4049/jimmunol.198.supp.210.13" @default.
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