Regulatory T cell heterogeneity: who they are, where they come from, and where they go

Regulatory T cells (Tregs) are essential for enforcing immune tolerance and homeostasis, but they comprise several distinct populations that differ in developmental origin, activation state, tissue adaptation, and functional specialization. These differences shape where Tregs reside, which immune responses they suppress, and how stable their lineage remains over time. This heterogeneity matters increasingly as immunology and therapeutics move from bulk Treg measurements toward subset- and context-specific interpretations. Treg-directed strategies now range from expanding Tregs to treat autoimmune disease to inhibiting tumor Tregs to enhance tumor immunity. In this review, we use three questions (who heterogeneous Tregs are, where they come from, and where they go) to organize recent advances that explain how Tregs are generated and maintained, how they traffic and adapt across tissues, and how their states shift across physiology and diseases. We also delineate Treg heterogeneity with a particular focus on contrasts between naïve Tregs (nTregs) and effector Tregs (eTregs), including defining markers and key biological features. We aim to provide a practical framework for interpreting human Treg datasets and for selectively using distinct Treg subsets in experimental design and therapeutic development.