2. Academic Validation
  3. Mycobacterium tuberculosis produces D-serine under hypoxia to limit CD8+ T cell-dependent immunity in mice

Mycobacterium tuberculosis produces D-serine under hypoxia to limit CD8+ T cell-dependent immunity in mice

  • Nat Microbiol. 2024 May 28. doi: 10.1038/s41564-024-01701-1.
Hongyu Cheng # 1 2,  Zhe Ji # 1 2,  Yang Wang 2,  Shenzhi Li 2,  Tianqi Tang 2,  Fei Wang 2,  Cheng Peng 2,  Xiangyang Wu 3,  Yuanna Cheng 2,  Zhonghua Liu 1,  Mingtong Ma 2,  Jie Wang 1,  Xiaochen Huang 1,  Lin Wang 1,  Lianhua Qin 1,  Haipeng Liu 3,  Jianxia Chen 3,  Ruijuan Zheng 1,  Carl G Feng 4 5,  Xia Cai 6,  Di Qu 6,  Lilin Ye 7,  Hua Yang 8 9,  Baoxue Ge 10 11 12
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, P. R. China.
  • 2 Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, PR China.
  • 3 Clinical and Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, P. R. 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 Biosafety Level 3 Laboratory, Shanghai Medical College, Fudan University, Shanghai, P. R. China.
  • 7 Institute of Immunology, Third Military Medical University, Chongqing, P. R. China. yelilinlcmv@tmmu.edu.cn.
  • 8 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, P. R. China. yanghua97065@163.com.
  • 9 Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, PR China. yanghua97065@163.com.
  • 10 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, P. R. China. gebaoxue@sibs.ac.cn.
  • 11 Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, PR China. gebaoxue@sibs.ac.cn.
  • 12 Clinical and Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, P. R. China. gebaoxue@sibs.ac.cn.
  • # Contributed equally.
PMID: 38806671 DOI: 10.1038/s41564-024-01701-1
Abstract

Adaptation to hypoxia is a major challenge for the survival of Mycobacterium tuberculosis (Mtb) in vivo. Interferon (IFN)-γ-producing CD8+ T cells contribute to control of Mtb Infection, in part by promoting antimicrobial activities of macrophages. Whether Mtb counters these responses, particularly during hypoxic conditions, remains unknown. Using metabolomic, proteomic and genetic approaches, here we show that Mtb induced Rv0884c (SerC), an Mtb phosphoserine aminotransferase, to produce D-serine. This activity increased Mtb pathogenesis in mice but did not directly affect intramacrophage Mtb survival. Instead, D-serine inhibited IFN-γ production by CD8+ T cells, which indirectly reduced the ability of macrophages to restrict Mtb upon co-culture. Mechanistically, D-serine interacted with WDR24 and inhibited mTORC1 activation in CD8+ T cells. This decreased T-bet expression and reduced IFN-γ production by CD8+ T cells. Our findings suggest an Mtb evasion mechanism where pathogen metabolic adaptation to hypoxia leads to amino acid-dependent suppression of adaptive anti-TB immunity.

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