Deciphering the developmental trajectory of tissue-resident Foxp3⁺ regulatory T cells

Foxp3⁺ T_REG cells have been at the focus of intense investigation for their recognized roles in preventing autoimmunity, facilitating tissue recuperation following injury, and orchestrating a tolerance to innocuous non-self-antigens. To perform these critical tasks, T_REG cells undergo deep epigenetic, transcriptional, and post-transcriptional changes that allow them to adapt to conditions found in tissues both at steady-state and during inflammation. The path leading T_REG cells to express these tissue-specialized phenotypes begins during thymic development, and is further driven by epigenetic and transcriptional modifications following TCR engagement and polarizing signals in the periphery. However, this process is highly regulated and requires T_REG cells to adopt strategies to avoid losing their regulatory program altogether. Here, we review the origins of tissue-resident T_REG cells, from their thymic and peripheral development to the transcriptional regulators involved in their tissue residency program. In addition, we discuss the distinct signalling pathways that engage the inflammatory adaptation of tissue-resident T_REG cells, and how they relate to their ability to recognize tissue and pathogen-derived danger signals.