He Kaixin, Wan Tingting, Wang Decai, Hu Ji, Zhou Tingyue, Tao Wanyin, Wei Zheng, Lu Qiao, Zhou Rongbin, Tian Zhigang, Flavell Richard A, Zhu Shu
Department of Digestive Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
Cell. 2023 Jul 6;186(14):3033-3048.e20. doi: 10.1016/j.cell.2023.05.027. Epub 2023 Jun 15.
The intestinal epithelial cells (IECs) constitute the primary barrier between host cells and numerous foreign antigens; it is unclear how IECs induce the protective immunity against pathogens while maintaining the immune tolerance to food. Here, we found IECs accumulate a less recognized 13-kD N-terminal fragment of GSDMD that is cleaved by caspase-3/7 in response to dietary antigens. Unlike the 30-kD GSDMD cleavage fragment that executes pyroptosis, the IEC-accumulated GSDMD cleavage fragment translocates to the nucleus and induces the transcription of CIITA and MHCII molecules, which in turn induces the Tr1 cells in upper small intestine. Mice treated with a caspase-3/7 inhibitor, mice with GSDMD mutation resistant to caspase-3/7 cleavage, mice with MHCII deficiency in IECs, and mice with Tr1 deficiency all displayed a disrupted food tolerance phenotype. Our study supports that differential cleavage of GSDMD can be understood as a regulatory hub controlling immunity versus tolerance in the small intestine.
肠道上皮细胞（IECs）构成宿主细胞与众多外来抗原之间的主要屏障；目前尚不清楚IECs如何在维持对食物免疫耐受的同时诱导针对病原体的保护性免疫。在此，我们发现IECs积累了一种较少被认识的GSDMD 13-kD N端片段，该片段在饮食抗原刺激下被caspase-3/7切割。与执行细胞焦亡的30-kD GSDMD切割片段不同，IECs积累的GSDMD切割片段易位至细胞核并诱导CIITA和MHCII分子的转录，进而在上段小肠诱导Tr1细胞。用caspase-3/7抑制剂处理的小鼠、具有对caspase-3/7切割具有抗性的GSDMD突变的小鼠、IECs中缺乏MHCII的小鼠以及缺乏Tr1的小鼠均表现出食物耐受表型破坏。我们的研究支持，GSDMD的差异性切割可被理解为控制小肠免疫与耐受的调控枢纽。
