AhR deficiency drives γδT17 cell activation via HSPA9/FBXW11-mediated NICD ubiquitination, exacerbating autoimmune inflammation

Interleukin-17 (IL-17)-producing γδ T cells (γδT17 cells) are critical drivers of autoimmune inflammations like psoriasis and colitis. Despite their well-established pathogenic role, the precise molecular triggers for γδT17 cell activation have remained largely elusive. Understanding these upstream factors is crucial for developing targeted therapies that can modulate these highly inflammatory immune responses and address the unmet needs in chronic autoimmune diseases.

Researchers investigated the role of aryl hydrocarbon receptor (AhR) in γδT17 cell activation using both genetic and pharmacological approaches. They utilized AhR-deficient mice and applied pharmacological modulators to either promote or suppress AhR activity. The impact on γδT17 cell activation was assessed, and the underlying molecular mechanisms were explored. To confirm the mechanistic findings, they pretreated mice with adeno-associated virus (AAV) expressing short hairpin RNA targeting Hspa9 (AAV-shHspa9) or Notch1 (AAV-shNotch1) in models of psoriasis-like dermatitis and colitis.

Aryl hydrocarbon receptor (AhR) levels were markedly reduced upon γδT17 cell activation. Consistently, AhR deficiency significantly promoted γδT17 cell activation, while pharmacological activation of AhR suppressed it. Mechanistically, AhR deficiency strengthened the competition of heat shock protein family A member 9 (HSPA9) with F-box and WD-40 domain protein 11 (FBXW11) for binding to the RBP-j-associated molecule (RAM) domain of the Notch intracellular domain (NICD). This impaired FBXW11-dependent NICD ubiquitination, leading to an increase in NICD occupancy at the Rorc enhancer, which ultimately drove γδT17 cell activation. This molecular pathway directly links AhR status to Rorc expression, a key transcription factor for IL-17 production. > AhR deficiency consistently increased the proportion of γδT17 cells and exacerbated disease severity in both psoriasis-like dermatitis mice and colitis mice, effects that were almost entirely reversed by pretreatment with either AAV-shHspa9 or AAV-shNotch1.