The tissue-resident regulatory T cell pool is shaped by transient multi-tissue migration and a conserved residency program. Bulk RNA-Seq profiling of mouse tissue Tregs.

The tissues are the site of many important immunological reactions, yet how the immune system is controlled at these sites remains opaque. Recent studies have identified Foxp3+ regulatory T cells (Tregs) in non-lymphoid tissues, with unique characteristics compared to lymphoid Tregs. However, tissue Tregs have not been considered holistically across tissues. Here we performed a systematic analysis of the Treg population residing in non-lymphoid organs throughout the body, revealing shared phenotypes, transient residency and common molecular dependencies. Tissue Tregs from different non-lymphoid organs shared T cell receptor (TCR) sequences, with functional capacity to drive multi-tissue Treg entry, and were tissue-agnostic on tissue homing. Together these results demonstrate that the tissue-resident Treg pool in most non-lymphoid organs, other than the gut, is largely constituted by broadly self-reactive Tregs, characterised by transient multi-tissue migration. This work suggests common regulatory mechanisms may allow pan-tissue Tregs to safeguard homeostasis across the body.