Authors
Yue He, Yilei Guo, Yuxin Shi, Xuanming Wan, Yanrong Zhu, Wenjie Zhang, Haochang Lin, Zhifeng Wei, Yufeng Xia, Yue Dai
Published in
Science advances. Volume 12. Issue 27. Pages eaef7793. Jul 03, 2026. Epub Jul 03, 2026.
Abstract
Despite the well-established role of interleukin-17 (IL-17)-producing γδ T cells (γδT17 cells) in autoimmune inflammations, key factors to trigger the activation of γδT17 cells remain largely unknown. Here, we show that aryl hydrocarbon receptor (AhR) is markedly reduced upon γδT17 cell activation. AhR deficiency and pharmacological activation promotes and suppresses γδT17 cell activation, respectively. Mechanistically, AhR deficiency strengthens heat shock protein family A member 9 (HSPA9)-mediated competition with F-box and WD-40 domain protein 11(FBXW11) for binding to RBP-j-associated molecule (RAM) domain of Notch intracellular domain (NICD), which impairs FBXW11-dependent NICD ubiquitination to increase NICD occupancy at the Rorc enhancer to drive γδT17 cell activation. Consistently, AhR deficiency increases the proportion of γδT17 cells and the disease severity in psoriasis-like dermatitis mice and colitis mice, which is almost entirely reversed by pretreatment with either adeno-associated virus (AAV)-shHspa9 or AAV-shNotch1. Collectively, these findings identify AhR deficiency as a key driver of aberrant γδT17 activation, uncover a γδT17 activation mechanism via HSPA9/FBXW11-mediated suppression of NICD ubiquitination, and provide a strong mechanistic basis for AhR agonists as therapeutics in autoimmune inflammations.
PMID:
42397918
Bibliographic data and abstract were imported from PubMed on 04 Jul 2026.
Read full publication at:
Please sign in
to see all details.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 3
- Comments 0