Arase Mitsuru, Murakami Mari, Kihara Takako, Kuwahara Ryuichi, Toyota Hironobu, Sumitani Naoki, Kinoshita Naohiko, Chen Kelvin Y, Yokoi Takehito, Motooka Daisuke, Okuzaki Daisuke, Zhao Yuhe, Miyazaki Hazuki, Ogino Takayuki, Hirota Seiichi, Ikeuchi Hiroki, Takeda Kiyoshi
Department of Microbiology and Immunology, Graduate School of Medicine, The University of Osaka, Osaka, Japan.
Immunology Frontier Research Center, The University of Osaka , Osaka, Japan.
J Exp Med. 2025 Nov 3;222(11). doi: 10.1084/jem.20242106. Epub 2025 Sep 4.
Tissue-resident memory T cells (TRM) remain in nonlymphatic barrier tissues for extended periods and are deeply involved in immune memory at the site of inflammation. Here, we employed multilayered single-cell analytic approaches including chromatin, gene, and protein profiling to characterize a unique CD4+ TRM subset present in the inflamed gut mucosa of Crohn's disease patients. We identified two key transcription factors, RUNX2 and BHLHE40, as regulators of pathologically relevant CD4+ TRM. These transcriptional regulators work together to induce distinct cellular properties of disease-specific TRM, such as cytotoxicity, T helper 1-effector activity, and tissue retention. Downregulation of RUNX2 and BHLHE40 in patient-derived gut CD4+ T cells resulted in the mitigation of the pathogenic phenotype of these cells. Conversely, the ectopic overexpression of both transcription factors in healthy donor-derived CD4+ T cells drove IFN-γ pathways and enhanced tissue residency. Our findings illuminate the transcriptional programs driving disease-specific T cell formation in Crohn's disease.
组织驻留记忆T细胞（TRM）长期存在于非淋巴屏障组织中，并深度参与炎症部位的免疫记忆。在此，我们采用了包括染色质、基因和蛋白质谱分析在内的多层单细胞分析方法，以表征克罗恩病患者炎症性肠黏膜中存在的一个独特的CD4+ TRM亚群。我们鉴定出两个关键转录因子RUNX2和BHLHE40，作为与病理相关的CD4+ TRM的调节因子。这些转录调节因子共同作用，诱导疾病特异性TRM的不同细胞特性，如细胞毒性、辅助性T细胞1效应活性和组织驻留。患者来源的肠道CD4+ T细胞中RUNX2和BHLHE40的下调导致这些细胞致病表型的减轻。相反，在健康供体来源的CD4+ T细胞中这两种转录因子的异位过表达驱动了IFN-γ通路并增强了组织驻留。我们的研究结果阐明了驱动克罗恩病中疾病特异性T细胞形成的转录程序。
