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Peer-reviewedCC BY 4.0Nature Communications

SIRPγ promotes CD8⁺ T cell exhaustion via metabolic-epigenetic reprogramming in tuberculous pleural effusion

  • Yuening Yang1
  • Qianqian Xue1
  • Sidao Wang1
  • Wenbei Peng1
  • Linlin Ye1
  • Bohan Yang1
  • Zihao Wang1
  • Xuan Xiang1
  • Haolei Wang1
  • Yiran Niu2
  • Hai Huang3
  • Chengqing Yang3
1 more authors
  • Qiong Zhou1
  1. 1Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  2. 2Department of Respiratory and Critical Care Medicine, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  3. 3Wuhan Pulmonary Hospital, Wuhan Institute for Tuberculosis Control, Wuhan, Hubei China
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Abstract

Previous studies have shown that signal regulatory protein γ (SIRPγ) is an important regulatory factor for T cell function. However, its expression and biological role in tuberculous pleural effusion (TPE) remain unknown. In this study, we find that the level of SIRPγ is significantly upregulated in TPE compared to non-TPE. Furthermore, we demonstrate SIRPγ involvement in TPE pathogenesis through the induction of CD8⁺ T cell exhaustion. Mechanistically, SIRPγ interacts with CD47 to activate the phosphatidylinositol 3/kinase-protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, leading to the upregulation of phosphoglycerate dehydrogenase (PHGDH) and the enhancement of serine metabolism. Serine, in turn, facilitates S-adenosylmethionine (SAM)-dependent trimethylation of histone H3 lysine 4 (H3K4me3) epigenetic modification at the NFATC2 locus. This modification, in coordination with TCR-induced calcium signaling, promotes NFATC2 activation, ultimately driving the expression of exhaustion-associated transcription factors and immunosuppressive receptors. Together, our findings identify SIRPγ as a regulator of CD8⁺ T cell exhaustion in TPE and suggest its potential as a predictive biomarker for TPE diagnosis.

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Cite

BibTeXRIS
BibTeX
@article{yang2026sirpγ,
  title = {{SIRPγ promotes CD8⁺ T cell exhaustion via metabolic-epigenetic reprogramming in tuberculous pleural effusion}},
  author = {Yuening Yang and Qianqian Xue and Sidao Wang and Wenbei Peng and Linlin Ye and Bohan Yang and Zihao Wang and Xuan Xiang and Haolei Wang and Yiran Niu and Hai Huang and Chengqing Yang and Qiong Zhou},
  journal = {Nature Communications},
  year = {2026},
  month = sep,
  doi = {10.1038/s41467-026-77779-4},
  url = {https://doi.org/10.1038/s41467-026-77779-4},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - SIRPγ promotes CD8⁺ T cell exhaustion via metabolic-epigenetic reprogramming in tuberculous pleural effusion
AU  - Yuening Yang
AU  - Qianqian Xue
AU  - Sidao Wang
AU  - Wenbei Peng
AU  - Linlin Ye
AU  - Bohan Yang
AU  - Zihao Wang
AU  - Xuan Xiang
AU  - Haolei Wang
AU  - Yiran Niu
AU  - Hai Huang
AU  - Chengqing Yang
AU  - Qiong Zhou
PY  - 2026
DA  - 2026/09/25
JO  - Nature Communications
DO  - 10.1038/s41467-026-77779-4
UR  - https://doi.org/10.1038/s41467-026-77779-4
AB  - Previous studies have shown that signal regulatory protein γ (SIRPγ) is an important regulatory factor for T cell function. However, its expression and biological role in tuberculous pleural effusion (TPE) remain unknown. In this study, we find that the level of SIRPγ is significantly upregulated in TPE compared to non-TPE. Furthermore, we demonstrate SIRPγ involvement in TPE pathogenesis through the induction of CD8⁺ T cell exhaustion. Mechanistically, SIRPγ interacts with CD47 to activate the phosphatidylinositol 3/kinase-protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, leading to the upregulation of phosphoglycerate dehydrogenase (PHGDH) and the enhancement of serine metabolism. Serine, in turn, facilitates S-adenosylmethionine (SAM)-dependent trimethylation of histone H3 lysine 4 (H3K4me3) epigenetic modification at the NFATC2 locus. This modification, in coordination with TCR-induced calcium signaling, promotes NFATC2 activation, ultimately driving the expression of exhaustion-associated transcription factors and immunosuppressive receptors. Together, our findings identify SIRPγ as a regulator of CD8⁺ T cell exhaustion in TPE and suggest its potential as a predictive biomarker for TPE diagnosis.
SN  - 2041-1723
ER  -