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

研究成果: Article査読

4 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)2542-2558.e18
ジャーナルCell
185
14
DOI
出版ステータスPublished - 2022 7月 7

ASJC Scopus subject areas

  • 生化学、遺伝学、分子生物学(全般)

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