Harnessing the biology of regulatory T cells to treat disease

Regulatory T (T_reg) cells are a suppressive subset of CD4⁺ T cells that maintain immune homeostasis and restrain inflammation. Three decades after their discovery, the promise of strategies to harness T_reg cells for therapy has never been stronger. Multiple clinical trials seeking to enhance endogenous T_reg cells or deliver them as a cell-based therapy have been performed and hint at signs of success, as well as to important limitations and unanswered questions. Strategies to deplete T_reg cells in cancer are also in active clinical testing. Furthermore, multi-dimensional methods to interrogate the biology of T_reg cells are leading to a refined understanding of T_reg cell biology and new approaches to harness tissue-specific functions for therapy. A new generation of T_reg cell clinical trials is now being fuelled by advances in nanomedicine and synthetic biology, seeking more precise ways to tailor T_reg cell function. This Review will discuss recent advances in our understanding of human T_reg cell biology, with a focus on mechanisms of action and strategies to assess outcomes of T_reg cell-targeted therapies. It highlights results from recent clinical trials aiming to enhance or inhibit T_reg cell activity in a variety of diseases, including allergy, transplantation, autoimmunity and cancer, and discusses ongoing strategies to refine these approaches.