The adoptive transfer of regulatory T cells is a promising strategy to prevent graft-versus-host disease after allogeneic bone marrow transplantation. Here, we use a major histocompatibility complex-mismatched mouse model to follow the fate of in vitro expanded donor regulatory T cells upon migration to target organs. Employing comprehensive gene expression and repertoire profiling, we show that they retain their suppressive function and plasticity after transfer. Upon entering non-lymphoid tissues, donor regulatory T cells acquire organ-specific gene expression profiles resembling tissue-resident cells and activate hallmark suppressive and cytotoxic pathways, most evidently in the colon, when co-transplanted with graft-versus-host disease-inducing conventional T cells. Dominant T cell receptor clonotypes overlap between organs and across recipients and their relative abundance correlates with protection efficacy. Thus, this study reveals donor regulatory T cell selection and adaptation mechanisms in target organs and highlights protective features of Treg to guide the development of improved graft-versus-host disease prevention strategies.

调节性T细胞的过继转移是预防同种异体骨髓移植后移植物抗宿主病的一种有前景的策略。在这里，我们使用主要组织相容性复合物不匹配的小鼠模型来追踪体外扩增的供体调节性 T 细胞迁移到靶器官后的命运。采用全面的基因表达和库分析，我们表明它们在转移后保留了抑制功能和可塑性。进入非淋巴组织后，供体调节性 T 细胞获得类似于组织驻留细胞的器官特异性基因表达谱，并激活标志性抑制和细胞毒性途径，当与诱导移植物抗宿主病的细胞共移植时，在结肠中最明显常规 T 细胞。显性 T 细胞受体克隆型在器官之间和受体之间重叠，其相对丰度与保护功效相关。因此，这项研究揭示了靶器官中供体调节性 T 细胞的选择和适应机制，并强调了 Treg 的保护特征，以指导改进移植物抗宿主疾病预防策略的开发。