Huisman Brooke D, Michelson Daniel A, Rubin Sara A, Kohlsaat Katherine, Gomarga Wilson, Fang Yuan, Lee Ji Myung, Del Nido Pedro, Nathan Meena, Benoist Christophe, Zon Leonard, Mathis Diane
Department of Immunology, Harvard Medical School, Boston, MA, USA.
Department of Immunology, Harvard Medical School, Boston, MA, USA; Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Boston, MA, USA; PhD Program in Immunology, Harvard Medical School, Boston, MA, USA.
Immunity. 2025 Jan 14;58(1):108-123.e7. doi: 10.1016/j.immuni.2024.11.025. Epub 2024 Dec 27.
Thymic mimetic cells are molecular hybrids between medullary-thymic-epithelial cells (mTECs) and diverse peripheral cell types. They are involved in eliminating autoreactive T cells and can perform supplementary functions reflective of their peripheral-cell counterparts. Current knowledge about mimetic cells derives largely from mouse models. To provide the high resolution that proved revelatory for mice, we performed single-cell RNA sequencing on purified mimetic-cell compartments from human pediatric donors. The single-cell profiles of individual donors were surprisingly similar, with diversification of neuroendocrine subtypes and expansion of the muscle subtype relative to mice. Informatic and imaging studies on the muscle-mTEC population highlighted a maturation trajectory suggestive of skeletal-muscle differentiation, some striated structures, and occasional cellular groupings reminiscent of neuromuscular junctions. We also profiled thymic mimetic cells from zebrafish. Integration of data from the three species identified species-specific adaptations but substantial interspecies conservation, highlighting the evolutionarily ancient nature of mimetic mTECs. Our findings provide a landscape view of human mimetic cells, with anticipated relevance in autoimmunity.
胸腺模拟细胞是髓质胸腺上皮细胞（mTECs）与多种外周细胞类型之间的分子杂交体。它们参与清除自身反应性T细胞，并能执行与其外周细胞对应物相关的补充功能。目前关于模拟细胞的知识主要来自小鼠模型。为了提供对小鼠具有启示意义的高分辨率信息，我们对来自人类儿科供体的纯化模拟细胞区室进行了单细胞RNA测序。各个供体的单细胞图谱惊人地相似，相对于小鼠，神经内分泌亚型多样化，肌肉亚型有所扩展。对肌肉 - mTEC群体的信息学和成像研究突出了一条成熟轨迹，提示骨骼肌分化、一些横纹结构以及偶尔出现的让人联想到神经肌肉接头的细胞聚集。我们还分析了斑马鱼的胸腺模拟细胞。来自这三个物种的数据整合确定了物种特异性适应，但也存在大量种间保守性，突出了模拟mTECs在进化上的古老性质。我们的研究结果提供了人类模拟细胞的全景图，有望与自身免疫相关。
