Hepatic leukemia factor directs tissue residency of proinflammatory memory CD4+ T cells

• 成果类型: Article
• 署名作者: Kiuchi, Masahiro; Nemoto, Masahiro; Yagyu, Hiroyuki; Aoki, Ami; Iwamura, Chiaki; Sugimoto, Hikaru; Masuo, Yuki; Morita, Hajime; Ma, Shuhe; Okuno, Yukiko; Hishiya, Takahisa; Tsuji, Kaori; Sasaki, Atsushi; Kokubo, Kota; Ohishi, Kanae; Shinmi, Rie; Sonobe, Yuri; Iinuma, Tomohisa; Yonekura, Syuji; Yokomizo, Tomomasa; Komatsu, Norio; Onodera, Atsushi; Okumura, Shinya; Ito, Takashi; Hatano, Etsuro; Tsuruyama, Tatsuaki; Kurashima, Yosuke; Mato, Naoko; Suzuki, Takuji; Kimura, Motoko Yagi; Motohashi, Shinichiro; Kawakami, Eiryo; Ueno, Hideki; Tumes, Damon J.; Hanazawa, Toyoyuki; Nakayama, Toshinori; Hirahara, Kiyoshi
• 署名单位: Chiba University; Yokohama City University; Niigata University; Chiba University; RIKEN; Kyoto University; Kyoto University; Kyoto University; Kyoto University; Chiba University; Chiba University; Tokyo Women's Medical University; Juntendo University; Chiba University; Chiba University; Kyoto University; Kyoto University; Chiba University; Jichi Medical University; Chiba University; Chiba University; Chiba University; Centre for Cancer Biology; Adelaide University; University of South Australia; SA Pathology; Adelaide University; University of Adelaide; Japan Science & Technology Agency (JST)
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adp0714
• 发表日期: 2025-12-11
• 页码: eadp0714
• 关键词: TRANSCRIPTION FACTOR BHLHE40; innate lymphoid-cells; hematopoietic stem; th2 cells; PROGRAMS; SPHINGOSINE-1-PHOSPHATE; persistence; EGRESS; MODEL

摘要

CD4+ tissue-resident memory T (TRM) cells contribute to host defense and to the pathogenesis of chronic inflammatory diseases, but the molecules that direct their differentiation are unknown. We found that the transcription factor hepatic leukemia factor (HLF) could direct the tissue residency program and function of CD4+ TRM cells. HLF simultaneously up-regulated tissue retention receptors, down-regulated tissue egress receptors, and promoted proinflammatory CD4+ TRM cells by inducing Bhlhe40, and all of these processes were associated with changes in chromatin accessibility. Genetic deletion of Hlf inhibited CD4+ TRM cell generation and ameliorated airway tissue inflammation in vivo. HLF+ CD4+ TRM cells isolated from inflamed airway tissue in humans had a tissue residency signature and expressed inflammatory cytokines. We conclude that HLF may act as a central regulator of proinflammatory CD4+ TRM cell development and function.