Thymic epithelial cells co-opt lineage-defining transcription factors to eliminate autoreactive T cells

Daniel A. Michelson, Koji Hase, Tsuneyasu Kaisho, Christophe Benoist, Diane Mathis

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Medullary thymic epithelial cells (mTECs) ectopically express thousands of peripheral-tissue antigens (PTAs), which drive deletion or phenotypic diversion of self-reactive immature T cells during thymic differentiation. Failure of PTA expression causes multiorgan autoimmunity. By assaying chromatin accessibility in individual mTECs, we uncovered signatures of lineage-defining transcription factors (TFs) for skin, lung, liver, and intestinal cells—including Grhl, FoxA, FoxJ1, Hnf4, Sox8, and SpiB—in distinct mTEC subtypes. Transcriptomic and histologic analyses showed that these subtypes, which we collectively term mimetic cells, expressed PTAs in a biologically logical fashion, mirroring extra-thymic cell types while maintaining mTEC identity. Lineage-defining TFs bound to mimetic-cell open chromatin regions and were required for mimetic cell accumulation, whereas the tolerogenic factor Aire was partially and variably required. Expression of a model antigen in mimetic cells sufficed to induce cognate T cell tolerance. Thus, mTECs co-opt lineage-defining TFs to drive mimetic cell accumulation, PTA expression, and self-tolerance.

Original languageEnglish
Pages (from-to)2542-2558.e18
JournalCell
Volume185
Issue number14
DOIs
Publication statusPublished - 2022 Jul 7

Keywords

  • Aire
  • T cell
  • Treg
  • autoimmunity
  • mTEC
  • microfold
  • mimetic cell
  • thymus
  • tolerance
  • transcription factor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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