2. Academic Validation
  3. Mycobacterium tuberculosis-derived linoleic acid increases regulatory T cell function to promote bacterial survival within macrophages

Mycobacterium tuberculosis-derived linoleic acid increases regulatory T cell function to promote bacterial survival within macrophages

  • Nat Microbiol. 2025 Nov;10(11):2949-2965. doi: 10.1038/s41564-025-02140-2.
Hongyu Cheng # 1 2,  Shenzhi Li # 1 2,  Hongjie Liu # 1,  Meiyi Yan # 3,  Jingxiang Wang # 2,  Jingping Huang 2,  Shanshan Liu 2,  Yifan Yang 2,  Xinyu Cao 2,  Pengfei Cui 2,  Yuanna Cheng 2,  Zhonghua Liu 1,  Jie Wang 1,  Xiaochen Huang 1,  Lin Wang 1,  Lianhua Qin 1,  Ruijuan Zheng 1,  Carl G Feng 4 5,  Qiang Zou 6,  Yicheng Sun 7,  Zhe Ji 8 9,  Hua Yang 10 11,  Baoxue Ge 12 13 14
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
  • 2 Key Laboratory of Pathogen-Host Interaction, Ministry of Education, Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, People's Republic of China.
  • 3 NHC Key Laboratory of Systems Biology of Pathogens, State Key Laboratory of Respiratory Health and Multimorbidity, National Institute of Pathogen Biology and Center for Tuberculosis Research, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China.
  • 4 Immunology and Host Defense Group, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
  • 5 Tuberculosis Research Program, Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia.
  • 6 Hongqiao International Institute of Medicine, Tongren Hospital & Shanghai Institute of Immunology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
  • 7 NHC Key Laboratory of Systems Biology of Pathogens, State Key Laboratory of Respiratory Health and Multimorbidity, National Institute of Pathogen Biology and Center for Tuberculosis Research, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China. sunyc@ipbcams.ac.cnyang.
  • 8 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China. jizhe@tongji.edu.cn.
  • 9 Key Laboratory of Pathogen-Host Interaction, Ministry of Education, Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, People's Republic of China. jizhe@tongji.edu.cn.
  • 10 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China. yanghua97065@tongji.edu.cn.
  • 11 Key Laboratory of Pathogen-Host Interaction, Ministry of Education, Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, People's Republic of China. yanghua97065@tongji.edu.cn.
  • 12 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China. gebaoxue@sibs.ac.cn.
  • 13 Key Laboratory of Pathogen-Host Interaction, Ministry of Education, Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, People's Republic of China. gebaoxue@sibs.ac.cn.
  • 14 Clinical Translation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China. gebaoxue@sibs.ac.cn.
  • # Contributed equally.
PMID: 41073667 DOI: 10.1038/s41564-025-02140-2
Abstract

Regulatory T (Treg) cells expand during Mycobacterium tuberculosis (Mtb) Infection and suppress T cell-mediated control. Whether Mtb actively contributes to this process is unclear. Here, using a genome-wide mutant library, we show that the expression of Mtb Rv1272c, an ATP-binding cassette transporter, increased under hypoxic conditions and promotes Mtb survival in vivo by increasing lecithin import, followed by the production and release of linoleic acid. Linoleic acid released by infected macrophages promoted surface trafficking of the immune checkpoint molecule cytotoxic T lymphocyte antigen 4 (CTLA-4) in Treg cells via the Ca²⁺ transporter ATP2a3. This in turn inhibited macrophage Reactive Oxygen Species production and promoted Mtb survival inside macrophages. Rv1272c-induced linoleic acid further promoted Mtb immune evasion by increasing CTLA-4 surface trafficking on Treg cells in vivo. Mechanistically, linoleic acid interacts with ATP2a3 in Treg cells and promotes mitochondria-associated endoplasmic reticulum (ER) membrane formation. This facilitates ER-to-mitochondria CA2+ transfer and depletion of CA2+ in the ER, and triggers store-operated calcium entry, thus elevating cytosolic CA2+ levels to increase CA2+-dependent CTLA-4 surface trafficking in Treg cells. These findings reveal that Mtb can use a metabolite to manipulate host responses and promote its intracellular survival.

Figures
Products
Inhibitors & Agonists
Other Products