Profiling of Tregs across tissues reveals plasticity in ST2 expression and hierarchies in tissue-specific phenotypes

Foxp3(+) regulatory T cells (Tregs) are critical mediators of peripheral tolerance and immune homeostasis and exert tissue-specific functions. In many nonlymphoid tissues, Tregs show enriched expression of the IL-33 receptor ST2. Through comprehensive profiling of murine ST2(+) and ST2(-) Tregs, we found that Treg transcriptomes and phenotypes formed a hierarchical relationship across tissues. Only a small core signature distinguished ST2(+) Tregs from ST2(-) Tregs across all tissues, and differences in transcriptional profiles were predominantly tissue-specific. We also identified unique, highly proliferative, circulating ST2(+) Tregs with high migratory potential. In adoptive transfers, both ST2(+) and ST2(-) Tregs seeded various host tissues and demonstrated plasticity in ST2 expression. Furthermore, Tregs from donor lungs were differentially recovered from host nonlymphoid tissues in an IL-33-dependent manner. In summary, our work identified tissue residency rather than ST2 expression as a primary driver of tissue Treg identity and highlights the unique, tissue-specific adaption of ST2(+) Tregs.