The transcription factor XBP1 in dendritic cells promotes the T <sub>H</sub> 2 cell response in airway allergy
Gui Yang, Xianhai Zeng, Xiao‐Rui Geng, Jiang‐Qi Liu, Jiang‐Qi Liu, Li‐Hua Mo, Xiang‐Qian Luo, Huazhen Liu, Yuan‐Yi Zhang, Li-Teng Yang, Qinmiao Huang, Xiaojun Xiao, J. Liu, J. Liu, Ling-Zhi Xu, Da‐Bo Liu, Xiao-Yu Liu, Zhi‐Qiang Liu, Ping–Chang Yang
Abstract
Dendritic cells (DCs) that express T cell immunoglobulin domain molecule-4 (TIM4), a cell surface receptor for phosphatidylserine, induce T helper 2 (T H 2) cell responses and allergic reactions. We elucidated the role of the transcription factor X-box–binding protein-1 (XBP1) in the induction of the T H 2 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 T H 2 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 T H 2 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 T H 2 cell–dependent inflammation or allergic diseases.