2026-03-26 九州大学
図. 細胞の分化段階におけるRORγt発現制御機構の違い（免疫細胞の分化初期段階においてCNS(※8)11へのアクセス性の担保がRORγt発現を誘導するために必要。一方、分化後期においてはCNS9への転写因子結合がILC3などの自然免疫系細胞のRORγt発現誘導および、RORγt陽性抗原提示細胞(APC)依存的な末梢制御性T細胞(pTreg) (※9)の分化に重要。）
＜関連情報＞
- https://www.kyushu-u.ac.jp/ja/researches/view/1449
- https://www.kyushu-u.ac.jp/f/65252/26_0325_03.pdf
- https://www.cell.com/immunity/fulltext/S1074-7613(26)00054-3
階層的なRorc(γt)シス調節カスケードがRORγt⁺自然免疫細胞の分化を統制する A hierarchical Rorc(γt) cis-regulatory cascade orchestrates differentiation of RORγt⁺ innate immune cells
Takuma Fukui ∙ Miyuki Watanabe ∙ Reo Kobayashi ∙ … ∙ Ichiro Taniuchi ∙ Satoshi Kojo ∙ Shinichiro Sawa
Immunity Published:March 24, 2026
DOI:https://doi.org/10.1016/j.immuni.2026.02.002
Highlights
- Sequential regulation by CNS11 and CNS9 governs RORγt expression in innate immune cells
- CNS11 priming in HSCs/MPPs is required for RORγt induction in peripheral immune cells
- CNS9-driven RORγt enhancement is primarily required for RORγt⁺ APC differentiation
- CNS9 is essential for control of type 2 immunity via pTreg cell induction by RORγt⁺ APCs
Summary
Beyond their well-established roles in type 3 immunity, RORγt+ innate immune cells are also essential for secondary lymphoid organ (SLO) formation and gut homeostasis. However, the transcriptional mechanisms governing RORγt expression in these cells, including group 3 innate lymphoid cells (ILC3s), lymphoid tissue inducer (LTi) cells, and antigen-presenting cells (APCs), remain largely unresolved. Here, we identified two key cis-regulatory elements within conserved non-coding sequences (CNS)9 and 11 in the Rorc locus, which were sequentially utilized during differentiation. Initially, Runx-binding sites in CNS11 established chromatin accessibility as early as the hematopoietic stem cell (HSC) stage. Disruption of this chromatin priming prevented subsequent transcriptional activation, thereby abolishing the initial induction of RORγt in these cells. At later stages, CNS9 played a critical role, particularly in the development of RORγt⁺ APCs, contributing to colonic peripheral Treg (pTreg) cell induction. This hierarchical transcriptional regulation was essential for SLO formation and postnatal type 3 immunity and for restraining excessive intestinal type 2 immune responses through pTreg cell induction.
