Nuclear HMGB1 is critical for CD8 T cell IFN-γ production and anti-tumor immunity

  • Cell Rep. 2024 Aug 27;43(8):114591. doi: 10.1016/j.celrep.2024.114591.
Zhiguang Xu  1 ,  Weiying Ma  2 ,  Ji Wang  1 ,  Haofan Chen  1 ,  Hui Li  3 ,  Zhinan Yin  4 ,  Jianlei Hao  5 ,  Kebing Chen  6
Affiliations
  • 1. Department of Spine Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China.
  • 2. Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China.
  • 3. School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China.
  • 4. Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, P.R. China; The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, Guangdong, P.R. China. Electronic address: [email protected].
  • 5. Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong, P.R. China; The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, Guangdong, P.R. China. Electronic address: [email protected].
  • 6. Department of Spine Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China. Electronic address: [email protected].
PMID: 39116204 DOI: 10.1016/j.celrep.2024.114591
Abstract

HMGB1 (high-mobility group box-1) has been extensively studied as a damage-associated molecular pattern, with secreted cytokine function. However, its regulation on T cells, especially the function in the nucleus, has not been elucidated. Here, we use conditional knockout (HMGB1-f/f; CD2-cre) mice and find that HMGB1 potentiates the proliferation and interferon gamma (IFN-γ) expression of CD8 T cells rather than CD4 T cells. Notably, nuclear, but not secreted, HMGB1 supports the expression of IFN-γ in CD8 T cells via directly regulating the activity of Eomes, the transcription factor for IFN-γ. Functional study shows that HMGB1 promotes the anti-tumor ability of CD8 T cells in vitro and in vivo. Finally, tumor environmental interleukin-7 promotes HMGB1 and IFN-γ production via fatty acid oxidation in CD8 T cells. Overall, we identify the role of nuclear HMGB1 in CD8 T cell differentiation and demonstrate that it plays an important role in the anti-tumor programs of CD8 T cells.

Keywords
CP: Cancer; CP: Immunology.
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