Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital, and Institute of Immunology, Jilin University, Changchun, China.
Columbia Center for Translational Immunology, Columbia University Medical Center, New York, United States.
Elife. 2022 Dec 1;11:e73677. doi: 10.7554/eLife.73677.
Transgenic CD47 overexpression is an encouraging approach to ameliorating xenograft rejection and alloresponses to pluripotent stem cells, and the efficacy correlates with the level of CD47 expression. However, CD47, upon ligation, also transmits signals leading to cell dysfunction or death, raising a concern that overexpressing CD47 could be harmful. Here, we unveiled an alternative source of cell surface CD47. We showed that extracellular vesicles, including exosomes, released from normal or tumor cells overexpressing CD47 (transgenic or native) can induce efficient CD47 cross-dressing on pig or human cells. Like the autogenous CD47, CD47 cross-dressed on cell surfaces is capable of interacting with SIRPα to inhibit phagocytosis. However, ligation of the autogenous, but not cross-dressed, CD47 induced cell death. Thus, CD47 cross-dressing provides an alternative source of cell surface CD47 that may elicit its anti-phagocytic function without transmitting harmful signals to the cells. CD47 cross-dressing also suggests a previously unidentified mechanism for tumor-induced immunosuppression. Our findings should help to further optimize the CD47 transgenic approach that may improve outcomes by minimizing the harmful effects of CD47 overexpression.
转染 CD47 过表达是一种有前途的方法，可以改善异种移植物排斥和多能干细胞同种反应，其疗效与 CD47 表达水平相关。然而，CD47 一旦被连接，也会传递导致细胞功能障碍或死亡的信号，这让人担心过表达 CD47 可能有害。在这里，我们揭示了细胞表面 CD47 的另一种来源。我们表明，来自过表达 CD47（转基因或天然）的正常或肿瘤细胞释放的细胞外囊泡，包括外泌体，可以诱导猪或人细胞上有效的 CD47 交叉染色。与自体 CD47 一样，表面交叉染色的 CD47 能够与 SIRPα 相互作用以抑制吞噬作用。然而，自体 CD47 的连接，但不是交叉染色的 CD47，诱导细胞死亡。因此，CD47 交叉染色提供了细胞表面 CD47 的另一种来源，它可以在不向细胞传递有害信号的情况下发挥其抗吞噬作用。CD47 交叉染色还提示了一种以前未被识别的肿瘤诱导免疫抑制机制。我们的发现应该有助于进一步优化 CD47 转基因方法，通过最小化 CD47 过表达的有害影响来提高疗效。
