The transcription factor XBP1 in dendritic cells promotes the TH2 cell response in airway allergy.

Science signaling 2023 Jun 27

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Dendritic cells (DCs) that express T cell immunoglobulin domain molecule-4 (TIM4), a cell surface receptor for phosphatidylserine, induce T helper 2 (TH2) cell responses and allergic reactions. We elucidated the role of the transcription factor X-box-binding protein-1 (XBP1) in the induction of the TH2 cell response through its role in generating TIM4+ DCs. We found that XBP1 was required for TIM4 mRNA and protein expression in airway DCs in response to the cytokine interleukin-2 (IL-2) and that this pathway was required for TIM4 expression on DCs in response to the allergens PM2.5 and Derf1. The IL-2-XBP1-TIM4 axis in DCs contributed to Derf1/PM2.5-induced, aberrant TH2 cell responses in vivo. An interaction between the guanine nucleotide exchange factor Son of sevenless-1 (SOS1) and the GTPase RAS promoted XBP1 and TIM4 production in DCs. Targeting the XBP1-TIM4 pathway in DCs prevented or alleviated experimental airway allergy. Together, these data suggest that XBP1 is required for TH2 cell responses by inducing the development of TIM4+ DCs, which depends on the IL-2-XBP1-SOS1 axis. This signaling pathway provides potential therapeutic targets for the treatment of TH2 cell-dependent inflammation or allergic diseases.

Citation

Gui Yang, Xian-Hai Zeng, Xiao-Rui Geng, Jiang-Qi Liu, Li-Hua Mo, Xiang-Qian Luo, Hua-Zhen Liu, Yuan-Yi Zhang, Li-Teng Yang, Qin-Miao Huang, Xiao-Jun Xiao, Jie Liu, Ling-Zhi Xu, Da-Bo Liu, Xiao-Yu Liu, Zhi-Qiang Liu, Ping-Chang Yang. The transcription factor XBP1 in dendritic cells promotes the TH2 cell response in airway allergy. Science signaling. 2023 Jun 27;16(791):eabm9454