Early life poses the challenge of establishing an immune system tolerant to self while still maintaining sensitivity to pathogens. Generation of a special wave of Foxp3+CD4+ regulatory T (Treg) cells during the first weeks of life is an important part of the strategy to meet this challenge. Little is known about how these cells are generated and maintain tolerance. Exploring the early lymph node environment, via temporally resolved, whole-tissue, single-cell RNA sequencing, we identified stromal cells as the most distinctive cell compartment perinatal Tregs encountered. Studies on T cell–deficient mice and mice enriched in autoreactive T cells revealed a role for perinatal Tregs in maintaining early stromal cell homeostasis largely, but not entirely, through control of local interferon responses.
