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 (Treg) cells in non-lymphoid tissues with unique characteristics compared with lymphoid Treg cells. However, tissue Treg cells have not been considered holistically across tissues. Here, we performed a systematic analysis of the Treg cell population residing in non-lymphoid organs throughout the body, revealing shared phenotypes, transient residency, and common molecular dependencies. Tissue Treg cells from different non-lymphoid organs shared T cell receptor (TCR) sequences, with functional capacity to drive multi-tissue Treg cell entry and were tissue-agnostic on tissue homing. Together, these results demonstrate that the tissue-resident Treg cell pool in most non-lymphoid organs, other than the gut, is largely constituted by broadly self-reactive Treg cells, characterized by transient multi-tissue migration. This work suggests common regulatory mechanisms may allow pan-tissue Treg cells to safeguard homeostasis across the body.

组织是许多重要免疫反应的场所，但免疫系统如何在这些部位进行控制仍然不透明。最近的研究发现，与淋巴 Treg 细胞相比，非淋巴组织中的 Foxp3 ⁺调节性 T (Treg) 细胞具有独特的特征。然而，组织 Treg 细胞尚未被跨组织全面考虑。在这里，我们对全身非淋巴器官中的 Treg 细胞群进行了系统分析，揭示了共有的表型、短暂驻留和常见的分子依赖性。来自不同非淋巴器官的组织 Treg 细胞共享 T 细胞受体 (TCR) 序列，具有驱动多组织 Treg 细胞进入的功能能力，并且在组织归巢方面与组织无关。总之，这些结果表明，除肠道外，大多数非淋巴器官中的组织驻留 Treg 细胞池主要由广泛的自身反应性 Treg 细胞组成，其特征是短暂的多组织迁移。这项工作表明，共同的调节机制可能允许泛组织 Treg 细胞维护全身的稳态。