National Academy of Sciences, Proceedings of the National Academy of Sciences, 13(118), 2021
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Significance Foxp3 + CD4 + regulatory T cells (Tregs) control both immune responses and tissue homeostasis. Dedicated Treg compartments occur in several nonlymphoid tissues—When, where, and how do they acquire specialized characteristics? A splenic Treg population expressing low levels of the transcription factor PPARγ contains precursors of Tregs in visceral adipose tissue. Since PPARγ, the “master regulator” of adipocyte differentiation, is required for the accumulation and function of Tregs in this tissue but not others, its expression in splenic precursors of adipose-tissue Tregs is not surprising. We show that the splenic PPARγ lo Treg population is transcriptionally heterogeneous and engenders Tregs in multiple additional nonlymphoid tissues. A general pool of splenic precursors of nonlymphoid-tissue Tregs opens possibilities for manipulating them experimentally or therapeutically.