T-bet+ CXCR3+ liver regulartory Tcells (Tregs) suppress Th1 inflammation and progression of metabolic dysfunction-associated fatty liver disease (MAFLD) 2363

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Abstract Description MAFLD, and its advanced form, metabolic dysfunction-associated steatohepatitis (MASH), affect 24% and 1.5%-6.5% U.S. adults, respectively. Obesity, driven by a Western diet (WD), drives MAFLD/MASH progression. CD4+ Foxp3+ Tregs suppress excessive inflammation and maintain tissue homeostasis. However, the role of Tregs in MAFLD/MASH progression remains controversial. We observed increased Tregs in mouse liver during the early stage of WD-induced MAFLD/MASH. Without Tregs, there is an increase in hepatic inflammation and liver damage. Th1 cells producing IFNγ were the dominant T helper cells in the liver, and their numbers, along with IFNγ levels, rose in the absence of Tregs, suggesting that Tregs suppress Th1-driven inflammation in MAFLD. Tregs are consist of distinct subsets defined by different transcription factors and cytokine/chemokine receptors. Interestingly, we identified two main liver Treg subsets: one expressing T-bet and CXCR3, and another expressing PPARg and ST2. In WD-fed Tbx21flox Foxp3-Cre mice, single-cell RNA-seq and flow cytometry identified a significant loss of the CXCR3+ Tregs but a marked increase in ST2+ Tregs, leading to an increase in liver T-bet+ IFNg+ Th1 cells with elevated liver inflammation and damage. Conversely, removing IFNg+ Th1 cells by deleting T-bet in T cells reduced liver inflammation and damage in mice fed with a WD. These results highlight T-bet+ CXCR3+ Tregs as a key regulator limiting Th1-mediated liver inflammation during MAFLD. Funding Sources R01DK128061; T32CA275777 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)

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