Background/Purpose: 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 during thymic differentiation, and their absence can lead to antigen-specific autoimmunity. Most existing knowledge about them derives from mice. This study aimed to characterize mimetic cells in humans and compare their diversity across species.

Methods: Human thymuses were obtained from pediatric donors undergoing cardiac surgery. Mimetic cells were purified cytofluorimetrically, and cellular shifts in mimetic cells across age, sex and disease state were quantified. Population-level and single-cell RNA-sequencing (RNA-seq) of human mimetic cells characterized their diversity, transcriptional profiles and relative proportions across age, sex and disease state. scRNA-seq of zebrafish thymuses permitted comparative transcriptomic analysis of mimetic cells in fish, mice and humans. Several human and zebrafish mimetic cell subtypes were visualized using immunofluorescence microscopy.

Results: Human mimetic cells were defined as PDPN-negative, CD104-negative, MHCII-low mTECs. Their relative proportions and transcriptional profiles were stable across the sexes and early life, though apparently variable in Down syndrome. scRNA-seq of human mimetic cells showed a diversity of mimetic cell subtypes, including mimetic cells resembling muscle, skin, lung and kidney ionocytes, neuroendocrine cells, tuft cells, and cochlear hair cells. Humans possessed an expansion of the muscle mimetic cell population and a diversification of neuroendocrine and ionocyte mimetic cells relative to mice. scRNA-seq of zebrafish thymuses revealed substantial conservation among mimetic cell subtypes in fish, mice and humans as well as species-specific subtypes, such as zebrafish ionocytes that regulate ion balance in aquatic life. Immunofluorescence microscopy verified the presence of muscle mimetic cells in situ within human and zebrafish thymuses and demonstrated their phenotypic mimicry of muscle-like striations.

Conclusion: Humans possess a diverse thymic mimetic cell repertoire analogous to that previously described in mice. Human-specific adaptations include an expansion of the muscle mimetic cell population and diversification of neuroendocrine and ionocyte mimetic cells. Mimetic cells are evolutionarily ancient, having been conserved from zebrafish to mouse to man. Muscle mimetic cells in particular are conserved in all three species and may be relevant to myasthenia gravis pathogenesis. Given their importance in mouse T-cell tolerance, mimetic cells are likely to play important roles in human T-cell tolerance and autoimmunity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/thymic-mimetic-cells-in-humans-mice-and-fish-are-evolutionarily-ancient-with-species-specific-adaptations/