Regulatory T cell transdifferentiation as a driver of obesity and diabetes.

Foxp3+ regulatory T (Treg) cells exhibit remarkable plasticity, enabling them to phenotypically and functionally adapt to diverse immune responses across tissues. However, this plasticity comes with the risk of lineage instability, including downregulation of Foxp3 and acquisition of pro-inflammatory effector programs. Although Treg transdifferentiation has been implicated in autoimmunity, its precise contribution to disease pathogenesis has remained incompletely understood. Recent advances in single-cell RNA and TCR sequencing provide evidence that, in visceral adipose tissue (VAT), the loss of Treg cells during obesity is driven by the selective transdifferentiation of thymus-derived Treg cells in response to local inflammatory stress. We propose that this process fuels chronic inflammation and may represent one pathway linking Treg instability to chronic VAT inflammation and metabolic dysfunction. Here, we summarize emerging evidence for Treg destabilization in VAT and discuss how local inflammatory and systemic metabolic cues may interact to drive this process, drawing conceptual parallels with autoimmune diseases, particularly type 1 diabetes.