DataSheet_1_Origin, phenotype and autoimmune potential of T cells in human immune system mice receiving neonatal human thymus tissue.pdf

Robust human immune system (HIS) mice are created using human fetal thymus tissue and hematopoietic stem cells (HSCs). A HIS mouse model using neonatal human thymus tissue and umbilical cord blood (CB) HSCs (NeoHu) was recently described. We improved the model by removing the native murine thymus, which can also generate human T cells, and demonstrated definitively the capacity of human T cells to develop in a grafted neonatal human thymus. Human T cells derived from the neonatal thymus tissue appeared in peripheral blood early post-transplantation and CB-derived T cells appeared later. Naïve T cells were demonstrated in peripheral blood but effector memory and T peripheral helper phenotypes predominated later, in association with development of autoimmunity in some animals. Treatment of thymus grafts with 2-deoxyglucose (2-DG) increased the proportion of stem cells derived from injected HSCs, delayed onset of autoimmune disease, reduced early T cell reconstitution, and reduced effector/memory T cell conversion. Younger neonatal human thymus tissue was associated with improved T cell reconstitution. While the NeoHu model bypasses the need for fetal tissue, it has yet to demonstrate equivalent reconstitution to fetal tissue, though 2-DG can improve results by removing native thymocytes prior to transplantation.

免疫健全的人源化免疫系统（human immune system, HIS）小鼠可通过人胎儿胸腺组织与造血干细胞（hematopoietic stem cells, HSCs）构建获得。近期已有研究报道了一种采用新生儿胸腺组织与脐带血（umbilical cord blood, CB）来源造血干细胞构建的HIS小鼠模型（下称NeoHu模型）。本研究通过移除宿主小鼠自身可生成人T细胞的内源胸腺，对该模型进行了优化，并明确证实了人T细胞可在移植的新生儿胸腺组织中发育分化。移植后早期，外周血中即可检测到源自新生儿胸腺组织的人T细胞，而脐带血来源的人T细胞出现时间相对较晚。外周血中可检测到初始T细胞（naïve T cell），但后期以效应记忆性T细胞与外周辅助T细胞表型为主，部分小鼠还出现了自身免疫症状。采用2-脱氧葡萄糖（2-deoxyglucose, 2-DG）处理胸腺移植物，可提升注射的造血干细胞来源的干细胞占比，延缓自身免疫疾病的发病时间，降低早期T细胞重建效率，并减少效应/记忆性T细胞的转化比例。采用更年轻的新生儿胸腺组织，可提升T细胞重建效果。尽管NeoHu模型无需使用胎儿组织，但其T细胞重建效果仍不及胎儿胸腺组织来源的模型，不过可通过在移植前清除内源胸腺细胞并辅以2-脱氧葡萄糖处理，改善其重建效果。