Hepatic leukemia factor directs tissue residency of proinflammatory memory CD4 <sup>+</sup> T cells
CD4<sup>+</sup> tissue-resident memory T (T<sub>RM</sub>) 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<sup>+</sup> T<sub>RM</sub> cells. HLF simultaneously up-regulated tissue retention receptors, down-regulated tissue egress receptors, and promoted proinflammatory CD4<sup>+</sup> T<sub>RM</sub> cells by inducing <i>Bhlhe40</i>, and all of these processes were associated with changes in chromatin accessibility. Genetic deletion of <i>Hlf</i> inhibited CD4<sup>+</sup> T<sub>RM</sub> cell generation and ameliorated airway tissue inflammation in vivo. HLF<sup>+</sup> CD4<sup>+</sup> T<sub>RM</sub> 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<sup>+</sup> T<sub>RM</sub> cell development and function.
Authors
- Takashi Ito (ORCID: https://orcid.org/0000-0002-5892-8317)
- Hajime Morita (ORCID: https://orcid.org/0009-0004-1911-4435)
- Toyoyuki Hanazawa (ORCID: https://orcid.org/0000-0001-9721-5662)
- Kota Kokubo (ORCID: https://orcid.org/0000-0001-6896-1981)
- Masahiro Kiuchi (ORCID: https://orcid.org/0000-0002-0227-4502)
- Norio Komatsu (ORCID: https://orcid.org/0000-0003-1880-9126)
- Kaori Tsuji (ORCID: https://orcid.org/0009-0000-6270-7106)
- Syuji Yonekura (ORCID: https://orcid.org/0000-0002-1408-9072)
- Kiyoshi Hirahara (ORCID: https://orcid.org/0000-0002-9128-9449)
- Yuri Sonobe
- Eiryo Kawakami (ORCID: https://orcid.org/0000-0001-9955-4342)
- Naoko Mato
- Yukiko Okuno (ORCID: https://orcid.org/0000-0002-3788-1513)
- Shinichiro Motohashi (ORCID: https://orcid.org/0000-0002-9332-3129)
- Takuji Suzuki (ORCID: https://orcid.org/0000-0002-7257-6792)
- Hideki Ueno (ORCID: https://orcid.org/0000-0001-7747-0738)
- Yuki Masuo (ORCID: https://orcid.org/0009-0007-3515-173X)
- Etsuro Hatano (ORCID: https://orcid.org/0000-0003-3407-1918)
- Damon J. Tumes (ORCID: https://orcid.org/0000-0001-5709-857X)
- Takahisa Hishiya (ORCID: https://orcid.org/0000-0001-7049-8615)
- K. Ohishi (ORCID: https://orcid.org/0009-0003-6194-2632)
- Tomohisa Iinuma (ORCID: https://orcid.org/0000-0002-9940-5520)
- Atsushi Onodera (ORCID: https://orcid.org/0000-0002-3715-9408)
- Masahiro Nemoto (ORCID: https://orcid.org/0000-0002-8413-2136)
- Hikaru Sugimoto (ORCID: https://orcid.org/0000-0002-6468-0127)
- Shinya Okumura
- Tatsuaki Tsuruyama (ORCID: https://orcid.org/0000-0002-3118-2826)
- Shuhe Ma (ORCID: https://orcid.org/0000-0002-2805-9448)
- Ami Aoki (ORCID: https://orcid.org/0000-0002-8785-5612)
- Hiroyuki Yagyu (ORCID: https://orcid.org/0000-0003-4336-9919)
- Yosuke Kurashima (ORCID: https://orcid.org/0000-0001-8588-4033)
- Rie Shinmi (ORCID: https://orcid.org/0009-0000-9831-8399)
- Tomomasa Yokomizo (ORCID: https://orcid.org/0000-0001-6157-2852)
- Motoko Y. Kimura (ORCID: https://orcid.org/0000-0002-5607-5066)
- Atsushi Sasaki (ORCID: https://orcid.org/0000-0001-6127-7714)
- Chiaki Iwamura (ORCID: https://orcid.org/0000-0003-3537-8073)
- Toshinori Nakayama
Institutions
- South Australia Pathology (AU)
- Jichi Medical University (JP)
- Chiba University (JP)
- University of South Australia (AU)
- Kyoto University (JP)
- Japan Agency for Medical Research and Development (JP)
- Juntendo University (JP)
- Chiba University Hospital (JP)
- Niigata University Medical and Dental Hospital (JP)
- Kyoto University of Education (JP)
- Tokyo Women's Medical University (JP)
- Centre for Cancer Biology (AU)
- RIKEN Center for Integrative Medical Sciences (JP)
- The University of Adelaide (AU)
- Niigata University (JP)
- Yokohama City University (JP)
Publication Details
- Journal
- Science
- Published
- 2025-12-11
- DOI
- https://doi.org/10.1126/science.adp0714
- Citations
- 1
- Primary Topic
- Liver physiology and pathology
- Type
- article
- Field-Weighted Citation Impact
- 1.32