Cross-species analyses of thymic mimetic cells reveal evolutionarily ancient origins and both conserved and species-specific elements

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. [Display omitted] •Human thymic mimetic cells mirror a diversity of peripheral cell types•Human mimetic cells include a massive expansion of muscle mTECs vis-à-vis mice•Imaging reveals striated muscle mTECs and groupings akin to neuromuscular junctions•Zebrafish mimetic cells include conserved and fish-specific subtypes Thymic mimetic cells are chimeras between medullary-thymic-epithelial cells (mTECs) and peripheral cell types. Huisman, Michelson, et al. perform high-resolution profiling of human mimetics, revealing a diversification of nerve and ionocyte mTECs and a massive expansion of muscle mTECs vis-à-vis mice. Comparison of human, mouse, and zebrafish mimetics reveals species-specific and species-conserved subtypes.