A team led by Professor Chi Tian from School of Life Science and Technology (SLST) at ShanghaiTech University proposed a new therapeutic strategy for IPEX-like disorders in a mouse model. They convert defective regulatory T cells (Treg) into super-activated Tregs (SuperTreg). The paper, entitled In situ conversion of defective Treg into SuperTreg cells to treat advanced IPEX-like disorders in mice, was published in Nature Communications on June 5, 2020.
Tregs are essential immune suppressing cells. Treg defects, typically resulting from single gene mutations in diverse genes, can cause the autoimmune disease known as IPEX(-like) syndromes. These syndromes are currently incurable, with death ensuing in infancy or childhood. The CRISPR/Cas technology has made it possible to correct the underlying mutations in situ in patients, which offers an attractive therapeutic strategy for the devastating disease. However, by the time of diagnosis, the disease is often very severe. Is it too late for gene therapy? Even if it is not too late, how many defective Tregs in the patients need to be repaired in order to achieve the therapeutic effect?
The team has previously found that Treg-specific knockout of Brg1 can impair Treg function and induce a fatal autoimmune disease similar to IPEX in mice. In this study, the researchers used a method they previously developed to restore Brg1 expression to varying degrees in the knockout mice. The results were unexpected: even when the mice were already very sick, restoring Brg1 expression in small portions (at little as 8%) of Tregs was sometimes sufficient to rescue the dying mice. The reason is that once re-expressed, Brg1, in conjunction with the high levels of pro-inflammatory factors in the severe inflammatory environment, rapidly hyperactivated the defective Tregs and converted them into extraordinarily powerful “SuperTregs”. Once produced, SuperTregs migrate promptly to inflamed tissues, efficiently killing pro-inflammatory immune cells and reversing Inflammation, which enabled the repair of damaged tissues and restoration of health. Thus, in situcorrection of the mutations in a small fraction of Tregs can suffice to achieve significant beneficial effects thanks to SuperTreg production. Importantly, as the inflammation subsided, SuperTregs gradually lost their powerful functions, thus avoiding excessive immunosuppression. These data suggest a simple, effective and safe therapy for IPEX(-like) syndromes that exploits the defective Tregs and severe inflammatory environment preexisting in the patients.
Ph.D. candidates Li Yongqin, Chen Yuxin and Mao Shaoshuai from SLST are the co-first authors, Professor Chi Tian is the corresponding author, and ShanghaiTech University is the first completion unit.
Paper link: https://rdcu.be/b4A5m
Brg1 re-expression allows complete recovery of dying mice
SuperTreg mechanism model