Aryl hydrocarbon receptor deficiency triggers the activation of γδT17 cells to exacerbate autoimmune inflammation.

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 <i>Rorc</i> 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)-sh<i>Hspa9</i> or AAV-sh<i>Notch1</i>. 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.