Immune rejection caused by mismatches in human leucocyte antigens (HLAs) remains a major obstacle to the success of allogeneic cell therapies. Current strategies for the generation of ‘universal’ immune-compatible cells, particularly the editing of HLA class I (HLA-I) genes or the modulation of proteins that inhibit natural killer cells, often result in genomic instability or cellular cytotoxicity. Here we show that a β₂-microglobulin super-enhancer (B2M-SE) that is responsive to interferon-γ is a critical regulator of the expression of HLA-I on mesenchymal stromal cells (MSCs). Targeted epigenetic repression of B2M-SE in MSCs reduced the surface expression of HLA-I below the threshold required to activate allogenic T cells while maintaining levels sufficient to evade cytotoxicity mediated by natural killer cells. In a humanized mouse model, the epigenetically edited MSCs demonstrated improved survival by evading the immune system, allowing them to exert enhanced therapeutic effects on LPS-induced acute lung injury. Targeted epigenetic repression of B2M-SE may facilitate the development of off-the-shelf cell sources for allogeneic cell therapy.

由人类白细胞抗原 （HLA） 错配引起的免疫排斥反应仍然是同种异体细胞疗法成功的主要障碍。当前产生“通用”免疫相容细胞的策略，特别是编辑 HLA I 类 （HLA-I） 基因或调节抑制自然杀伤细胞的蛋白质，通常会导致基因组不稳定或细胞毒性。在这里，我们表明对干扰素 γ 反应的 β₂-微球蛋白超级增强子 （B2M-SE） 是间充质基质细胞 （MSC） 上 HLA-I 表达的关键调节因子。MSC 中 B2M-SE 的靶向表观遗传抑制将 HLA-I 的表面表达降低到激活同种异体 T 细胞所需的阈值以下，同时保持足以逃避自然杀伤细胞介导的细胞毒性的水平。在人源化小鼠模型中，表观遗传编辑的 MSC 通过逃避免疫系统证明了更高的生存率，使它们能够对 LPS 诱导的急性肺损伤发挥增强的治疗作用。B2M-SE 的靶向表观遗传抑制可能促进用于同种异体细胞治疗的现成细胞来源的开发。