*Purpose: CD4+CD25+Foxp3+ Tregs are known to acquire tissue-specific features and develop cytoprotective and regenerative functions. The extent to which this applies to liver-resident Tregs is unknown. In this study, we aimed to explore the phenotypic and functional diversity of liver resident Tregs during homeostasis. Additionally, we investigated their role in ameliorating liver inflammation and tissue damage in murine models by either depleting them or increasing their number through exogenous administration of IL-2 complexes (IL-2c).

*Methods: Flow cytometry phenotyping and microarray analysis was performed on Foxp3-YFP intrahepatic and splenic Tregs in homeostatic conditions and after the administration of IL-2c for 3 consecutive days. Tregs were depleted in Foxp3-DTR mice by intraperitoneal (i.p) injection of 1ug diphtheria toxin and IL-2c were administered i.p. to wild-type C57BL/6 mice. The extent of liver damage after a single dose of carbon tetrachloride (CCL4) was investigated in both models.

*Results: Quantifying Foxp3+CD4+ cells among different tissues showed that the liver exhibited the lowest abundance of Tregs. Analysis in homeostatic conditions revealed that, although intrahepatic Tregs exhibited the core transcriptional Treg signature, they expressed a distinct transcriptional profile. This was characterized by reduced CD25 expression and increased levels of pro-inflammatory Th1-related transcripts. Depletion of Tregs effectively reduced the magnitude of systemic and intra-hepatic inflammatory responses following CCL4 injury, but they did not influence the degree of hepatocyte necrosis. In contrast, the administration of IL-2c markedly increased the number of intra-hepatic Tregs and significantly ameliorated liver damage following CCl4 administration. The cytoprotective effect observed in response to IL-2c was associated with increased expression of markers known to regulate Treg suppressive function.

*Conclusions: Our results offer insight into the transcriptome and complex immune network of intrahepatic Tregs and suggest that strategies capable of selectively increasing the pool of intra-hepatic Tregs could constitute effective therapies in inflammatory liver diseases.

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