Developmental Heterogeneity of Foxp3⁺ Regulatory T Cells in the Orchestration of Metabolic Homeostasis

Regulatory T (Treg) cells were first identified through the observation that Foxp3 gene mutations in mice and humans can result in their dysfunction, leading to a catastrophic multi-organ autoimmune syndrome. Since then, it has become increasingly evident that Foxp3⁺ Treg cells serve functions extending well beyond dominant tolerance and the mere prevention of autoimmune pathology. Highlighting their pivotal role in metabolic regulation, dysfunction of Treg cells has been implicated in the pathogenesis of both type 1 and type 2 diabetes. Emerging evidence further suggests that Treg cells contribute to tissue homeostasis and regeneration by facilitating repair processes, modulating immune responses to curb excessive inflammation, and supporting stem cell function in key metabolic organs such as muscle, adipose tissue, and the liver. This review aims to highlight recent progress in elucidating the functional specialization of Treg cells in the regulation of metabolic homeostasis. It explores the distinct roles of thymic and peripheral Treg cells in constraining pancreatic β-cell autoimmunity and the inflammation of metabolic organs, while also underscoring the pathogenic potential of Treg cell instability and their dedifferentiation into pathogenic effector cells. Investigating the roles of thymic and peripheral Treg cells in both forms of diabetes is a valuable endeavor, offering insight into their distinct and shared contributions to disease progression, while shedding light on immune dysregulation, metabolic inflammation, and immune-metabolic crosstalk. These insights may provide a foundation for the development of targeted therapeutic approaches directed at specific Treg cell subsets, offering the potential to attenuate disease progression or even entirely prevent its onset.