Thirty years in, regulatory T cells are ready for medicine.

Regulatory T (Treg) cells are a specialized subset of CD4+ T cells indispensable for the establishment and maintenance of immunological tolerance. Treg cells employ diverse mechanisms of immune regulation mediated by a broad repertoire of immunosuppressive molecules under the control of the lineage-specifying transcription factor FoxP3. Functional defects in Treg cells disrupt immune homeostasis and are implicated in the pathogenesis of autoimmune diseases, chronic inflammatory disorders, and cancer. In this article, we revisit three decades of progress since Sakaguchi's seminal discovery of CD25+ regulatory T cells in 1995, highlighting the physiological significance of dominant immune tolerance and its underlying molecular mechanisms. We then discuss how these mechanisms have inspired therapeutic strategies aimed at enhancing or harnessing Treg cell function, the remaining challenges and recent technological advances toward clinical translation, and the near-future prospects for Treg-based therapies in immune-mediated diseases.