RORγt expression in mature T<sub>H</sub>17 cells safeguards their lineage specification by inhibiting conversion to T<sub>H</sub>2 cells.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 36026450.
- Also identified by DOI 10.1126/sciadv.abn7774 and PMC identifier 9417185.
- Licence recorded as CC BY-NC.
- Because redistribution is not established, this page shows the abstract only. Follow the links below for the full text.
Abstract
RORγt is the lineage-specific transcription factor for T helper 17 (T<sub>H</sub>17) cells and an attractive drug target for treating T<sub>H</sub>17-associated diseases. Although the critical role of RORγt in early T<sub>H</sub>17 cell differentiation has been well recognized, its function in mature T<sub>H</sub>17 cell maintenance remains largely unknown. Here, we show that genetic deletion of <i>Rorc</i> in mature T<sub>H</sub>17 cells inhibited their pathogenic functions. Mechanistically, loss of RORγt led to a closed chromatin configuration at key T<sub>H</sub>17-specific gene loci, particularly at the "super-enhancer" regions. Unexpectedly, RORγt directly bound and inhibited <i>Il4</i> transcription, whereas pharmaceutically or genetically targeting RORγt caused spontaneous conversion of T<sub>H</sub>17 cells to T<sub>H</sub>2-like cells in vitro and in vivo. Our results thus reveal dual crucial functions of RORγt in effector T<sub>H</sub>17 cells in maintaining T<sub>H</sub>17 cell program and constraining T<sub>H</sub>2 cell conversion, offering previously unidenified considerations in therapeutic targeting of RORγt.
Medical subject headings
- Nuclear Receptor Subfamily 1, Group F, Member 3
- Th17 Cells