International immunopharmacology · 2026
Stabilization of MHCII on dendritic cells via AhR-mediated blockade of proteasomal degradation drives Th17 responses to exogenous antigens.
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Xie Huancheng, Wu Hanxi, Wang Jing, Li Linmei, He Ying, Wang Ying, Huang Yuyi, Yan Jie, Sun Weimin, Tao Ailin
Аннотация
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.
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.