Regulatory T cells (Tregs) are crucial immune cells for tissue repair and regeneration. However, their potential as a cell-based regenerative therapy is not yet fully understood. Here, we show that local delivery of exogenous Tregs into injured mouse bone, muscle, and skin greatly enhances tissue healing. Mechanistically, exogenous Tregs rapidly adopt an injury-specific phenotype in response to the damaged tissue microenvironment, upregulating genes involved in immunomodulation and tissue healing. We demonstrate that exogenous Tregs exert their regenerative effect by directly and indirectly modulating monocytes/macrophages (Mo/MΦ) in injured tissues, promoting their switch to an anti-inflammatory and pro-healing state via factors such as interleukin (IL)-10. Validating the key role of IL-10 in exogenous Treg-mediated repair and regeneration, the pro-healing capacity of these cells is lost when Il10 is knocked out. Additionally, exogenous Tregs reduce neutrophil and cytotoxic T cell accumulation and IFN-γ production in damaged tissues, further dampening the pro-inflammatory Mo/MΦ phenotype. Highlighting the potential of this approach, we demonstrate that allogeneic and human Tregs also promote tissue healing. Together, this study establishes exogenous Tregs as a possible universal cell-based therapy for regenerative medicine and provides key mechanistic insights that could be harnessed to develop immune cell-based therapies to enhance tissue healing.

调节性 T 细胞 (Treg) 是组织修复和再生的关键免疫细胞。然而，它们作为基于细胞的再生疗法的潜力尚未完全了解。在这里，我们发现将外源性 Tregs 局部递送到受伤的小鼠骨骼、肌肉和皮肤中可以极大地增强组织愈合。从机制上讲，外源性 Tregs 会迅速采取损伤特异性表型来响应受损的组织微环境，上调参与免疫调节和组织愈合的基因。我们证明外源性 Tregs 通过直接和间接调节受损组织中的单核细胞/巨噬细胞 (Mo/MΦ) 发挥再生作用，通过白细胞介素 (IL)-10 等因子促进其转变为抗炎和促愈合状态。验证了 IL-10 在外源性 Treg 介导的修复和再生中的关键作用，当IL10被敲除时，这些细胞的促愈合能力就会丧失。此外，外源性 Tregs 会减少受损组织中中性粒细胞和细胞毒性 T 细胞的积累以及 IFN-γ 的产生，进一步抑制促炎 Mo/MΦ 表型。我们强调了这种方法的潜力，证明同种异体和人类 Tregs 也能促进组织愈合。总之，这项研究将外源性 Tregs 确立为一种可能的通用的基于细胞的再生医学疗法，并提供了关键的机制见解，可用于开发基于免疫细胞的疗法以增强组织愈合。