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

Brooke D Huisman; Daniel A Michelson; Sara A Rubin; Katherine Kohlsaat; Wilson Gomarga; Yuan Fang; Ji Myung Lee; Pedro Del Nido; Meena Nathan; Christophe Benoist; Leonard Zon; Diane Mathis

doi:10.1016/j.immuni.2024.11.025

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

Immunity. 2024 Dec 18:S1074-7613(24)00540-5. doi: 10.1016/j.immuni.2024.11.025. Online ahead of print.

Authors

Affiliations

¹ Department of Immunology, Harvard Medical School, Boston, MA, USA.
² 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.
³ Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Boston, MA, USA; PhD Program in Immunology, Harvard Medical School, Boston, MA, USA; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
⁴ Department of Cardiac Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
⁶ Department of Cardiac Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Harvard Medical School, Boston, MA, USA.
⁷ Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA; Howard Hughes Medical Institute and Boston Children's Hospital, Boston, MA, USA.
⁸ Department of Immunology, Harvard Medical School, Boston, MA, USA. Electronic address: [email protected].

PMID: 39731911
DOI: 10.1016/j.immuni.2024.11.025

Abstract

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.

Keywords: T cell; autoimmunity; human; immunological tolerance; medullary-thymic-epithelial cell; muscle; myasthenia gravis; neuromuscular junction; thymus; zebrafish.