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Peer-reviewedCC BY 4.0The Journal of Clinical Investigation

Enhancing Treg persistence by inhibiting necroptosis restrains autoimmune pathology

  • Qiaoyan Wu1,2
  • Na Cui1
  • Li Gao3
  • Zhihui Lu1,2
  • Xiang Ao1,2
  • Rui Pang4,5
  • Xingyan Li1
  • Heling Pan1
  • Daichao Xu1,6
  • Peiying Li4,5
  • Junying Yuan1,6
  • Chengyu Zou1,6
6 affiliations
  1. 1Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  2. 2University of Chinese Academy of Sciences, Beijing, China.
  3. 3Department of Neurology, and
  4. 4Department of Anesthesiology, Key Laboratory of the Ministry of Education, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  5. 5Clinical Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  6. 6Shanghai Key Laboratory of Aging Studies, Shanghai, China.
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Abstract

Regulatory T cells (Tregs) hold great promise as next-generation therapeutics for autoimmune diseases. However, maintaining their functional persistence within inflamed tissues remains a major translational challenge. Using an in vitro system that recapitulates the inflammatory CNS milieu of multiple sclerosis (MS), together with a pooled shRNA screen, we identify necroptotic signaling as a key driver of Treg death, thereby compromising Treg functional persistence under inflammatory conditions. We further demonstrate that Tregs in both a mouse model of MS and patients with MS exhibited a preferential susceptibility to receptor-interacting serine/threonine kinase 1–dependent (RIPK1-dependent) necroptosis. Mechanistically, a FOXP3-driven, low-glucose metabolic program rendered Tregs intrinsically susceptible to necroptosis by limiting O-GlcNAcylation (O-GlcNAc) modification on RIPK1. This vulnerability was not shared by conventional T cells under comparable inflammatory conditions. Finally, in combination with adoptive Treg transfer, we show that selective inhibition of necroptosis in Tregs enhanced their survival and suppressive function at sites of active inflammation, thereby reducing autoimmune pathology in mouse models of MS and systemic lupus erythematosus. Together, these findings identify necroptotic cell death as a barrier to Treg persistence within inflamed tissues and highlight the therapeutic potential of necroptosis-resistant Tregs for the treatment of autoimmune diseases.

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Cite

BibTeXRIS
BibTeX
@article{wu2026enhancing,
  title = {{Enhancing Treg persistence by inhibiting necroptosis restrains autoimmune pathology}},
  author = {Qiaoyan Wu and Na Cui and Li Gao and Zhihui Lu and Xiang Ao and Rui Pang and Xingyan Li and Heling Pan and Daichao Xu and Peiying Li and Junying Yuan and Chengyu Zou},
  journal = {The Journal of Clinical Investigation},
  year = {2026},
  month = sep,
  doi = {10.1172/jci207077},
  url = {https://doi.org/10.1172/jci207077},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Enhancing Treg persistence by inhibiting necroptosis restrains autoimmune pathology
AU  - Qiaoyan Wu
AU  - Na Cui
AU  - Li Gao
AU  - Zhihui Lu
AU  - Xiang Ao
AU  - Rui Pang
AU  - Xingyan Li
AU  - Heling Pan
AU  - Daichao Xu
AU  - Peiying Li
AU  - Junying Yuan
AU  - Chengyu Zou
PY  - 2026
DA  - 2026/09/01
JO  - The Journal of Clinical Investigation
DO  - 10.1172/jci207077
UR  - https://doi.org/10.1172/jci207077
AB  - Regulatory T cells (Tregs) hold great promise as next-generation therapeutics for autoimmune diseases. However, maintaining their functional persistence within inflamed tissues remains a major translational challenge. Using an in vitro system that recapitulates the inflammatory CNS milieu of multiple sclerosis (MS), together with a pooled shRNA screen, we identify necroptotic signaling as a key driver of Treg death, thereby compromising Treg functional persistence under inflammatory conditions. We further demonstrate that Tregs in both a mouse model of MS and patients with MS exhibited a preferential susceptibility to receptor-interacting serine/threonine kinase 1–dependent (RIPK1-dependent) necroptosis. Mechanistically, a FOXP3-driven, low-glucose metabolic program rendered Tregs intrinsically susceptible to necroptosis by limiting O-GlcNAcylation (O-GlcNAc) modification on RIPK1. This vulnerability was not shared by conventional T cells under comparable inflammatory conditions. Finally, in combination with adoptive Treg transfer, we show that selective inhibition of necroptosis in Tregs enhanced their survival and suppressive function at sites of active inflammation, thereby reducing autoimmune pathology in mouse models of MS and systemic lupus erythematosus. Together, these findings identify necroptotic cell death as a barrier to Treg persistence within inflamed tissues and highlight the therapeutic potential of necroptosis-resistant Tregs for the treatment of autoimmune diseases.
SN  - 0021-9738
SN  - 1558-8238
ER  -