Control of medullary thymic epithelial cell development and central tolerance by a zinc finger transcription factor

Abstract

Abstract We have identified a novel function for a zinc finger transcription factor in medullary thymic epithelial cell (mTEC) development and central tolerance. Previous studies have shown that the transcription factor has critical functions in immune cell development, however our study is one of the first to describe a role for the transcription factor in the epithelial lineage. Probing publicly available gene expression databases, we found that the transcription factor is highly expressed in mTECs. Recent studies on mTECs have shown considerable cellular heterogeneity within mTECs with at least five mTEC subtypes including a transient amplifying population (TAC-TECs), autoimmune regulator (Aire+) mTECs, Late/Post Aire mTECs, Ccl21a mTECS, and tuft cells. Using a conditional knockout mouse line, we deleted the transcription factor in mTECs which resulted in drastic changes in the cellular composition of mTECs with substantial increase in Ccl21a mTECs and tuft cells and a dramatic decrease in Aire+ mTECs and Late Aire mTECs. Furthermore, the remaining Aire+ mTECs have a significant decrease in tissue-specific antigen gene expression resulting in autoimmunity in mice. To gain mechanistic understanding of the developmental changes we observed, we performed scRNA-seq and scATAC-seq, which showed significant changes in gene expression and the chromatin landscape in mTECs and helps to explain the critical function for this transcription factor in mTEC development.