The immunosuppressive activity of mesenchymal stromal cells (MSCs) is well documented. However, the therapeutic benefit is completely unpredictable, thus raising concerns about MSC efficacy. One of the affecting factors is the unresolved conundrum that, despite being immunosuppressive, MSCs are undetectable after administration. Therefore, understanding the fate of infused MSCs could help predict clinical responses. Using a murine model of graft-versus-host disease (GvHD), we demonstrate that MSCs are actively induced to undergo perforin-dependent apoptosis by recipient cytotoxic cells and that this process is essential to initiate MSC-induced immunosuppression. When examining patients with GvHD who received MSCs, we found a striking parallel, whereby only those with high cytotoxic activity against MSCs responded to MSC infusion, whereas those with low activity did not. The need for recipient cytotoxic cell activity could be replaced by the infusion of apoptotic MSCs generated ex vivo. After infusion, recipient phagocytes engulf apoptotic MSCs and produce indoleamine 2,3-dioxygenase, which is ultimately necessary for effecting immunosuppression. Therefore, we propose the innovative concept that patients should be stratified for MSC treatment according to their ability to kill MSCs or that all patients could be treated with ex vivo apoptotic MSCs.

间充质基质细胞（MSC）的免疫抑制活性已有充分记录。然而，治疗效果是完全不可预测的，因此引起了人们对 MSC 疗效的担忧。影响因素之一是尚未解决的难题，即尽管具有免疫抑制作用，但给药后 MSC 仍无法检测到。因此，了解输注间充质干细胞的命运有助于预测临床反应。使用移植物抗宿主病 (GvHD) 的小鼠模型，我们证明 MSC 被受体细胞毒性细胞主动诱导发生穿孔素依赖性细胞凋亡，并且该过程对于启动 MSC 诱导的免疫抑制至关重要。当检查接受 MSC 的 GvHD 患者时，我们发现了一个惊人的相似之处，即只有那些对 MSC 具有高细胞毒活性的患者才会对 MSC 输注产生反应，而那些活性低的患者则不会。对受体细胞毒性细胞活性的需求可以通过输注离体产生的凋亡 MSC 来代替。输注后，受体吞噬细胞吞噬凋亡的 MSC 并产生吲哚胺 2,3-双加氧酶，这最终是实现免疫抑制所必需的。因此，我们提出了一个创新概念，即应根据患者杀死 MSC 的能力对患者进行分层治疗，或者所有患者都可以接受离体凋亡 MSC 治疗。