Stabilization of MHCII on dendritic cells via AhR-mediated blockade of proteasomal degradation drives Th17 responses to exogenous antigens

  • Int Immunopharmacol. 2026 Sep 15:185:117011. doi: 10.1016/j.intimp.2026.117011.
Huancheng Xie  1 ,  Hanxi Wu  1 ,  Jing Wang  1 ,  Linmei Li  1 ,  Ying He  1 ,  Ying Wang  1 ,  Yuyi Huang  1 ,  Jie Yan  2 ,  Weimin Sun  3 ,  Ailin Tao  4
Affiliations
  • 1. The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, The State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 250 Changgang Road East, Guangzhou 510260, China.
  • 2. The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, The State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 250 Changgang Road East, Guangzhou 510260, China. Electronic address: [email protected].
  • 3. Department of Laboratory Medicine, The Seventh Affiliated Hospital of Southern Medical University, Foshan, China. Electronic address: [email protected].
  • 4. The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, The State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 250 Changgang Road East, Guangzhou 510260, China. Electronic address: [email protected].
PMID: 42284760 DOI: 10.1016/j.intimp.2026.117011
Abstract

Background: Dendritic cells (DCs) activate CD4+ T cells by presenting antigens via MHCII. MHCII surface levels are regulated by diverse mechanisms, including ubiquitination. The Aryl Hydrocarbon Receptor (AhR) further modulates MHCII expression and DC function. Whether monocyte-derived dendritic cells (mo-DCs) regulate antigen presentation by sensing exogenous antigens through the AhR remains unclear.

Methods: Human THP1-DCs or murine BMDCs were treated with exogenous antigens, AhR antagonist CH223191, shRNA knockdown (AhR/IL4I1/CD83), AhR overexpression, or inhibitor (MG132/chloroquine/NH4Cl). Assessments included flow cytometry (MHCII/CD83/CD86), DC-T co-cultures (Th17 differentiation), qPCR, immunoblotting, tryptophan metabolite profiling (LC-MS/MS) and ELISA. In vivo, rPEA-exposed C57BL/6 mice received intratracheal CH223191, with analysis of lung DCs, IL-17A+ cells, BALF, and histopathology.

Results: Exogenous antigens (rPEA, OVA, Bet v 1) activated the AhR pathway in mo-DCs, upregulating AhR and downstream target genes (CYP1A1, AHRR). AhR regulates MHCII (HLA-DR) and CD86 membrane expression, with HLA-DR more affected. Antigen stimulation triggered tryptophan metabolism to produce AhR ligands, such as the metabolite indole-3-lactic acid produced by IL4I1. AhR activation sustained elevated surface HLA-DR by blocking proteasome-dependent degradation-independent of the newly synthesized MHCII-partially via CD83. AhR inhibition impaired mo-DC antigen presentation to CD4+ T cells and blocked Th17 differentiation in vitro. In mice, CH223191 attenuated rPEA-induced lung inflammation, reducing immune cell infiltration, IL-17A+ cells, and MHCII on CD11b+CD103- DCs in lymph nodes.

Conclusions: Exogenous antigens induce DC tryptophan metabolism, elevating AhR ligands. Activated AhR upregulates CD83 and blocks proteasomal degradation, sustaining the surface MHCII to drive Th17 responses. AhR inhibition modulates DC-mediated immunity and suppresses inflammatory pathology.

Keywords
Antigen; Aryl hydrocarbon receptor; Dendritic cells; Major histocompatibility complex class II; Tryptophan metabolism.
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