Enhancing Treg persistence by inhibiting necroptosis restrains autoimmune pathology
Qiaoyan Wu, Na Cui, Li Gao, Zhihui Lu, Xiang Ao, Rui Pang, Xingyan Li, Heling Pan, Daichao Xu, Peiying Li, Junying Yuan, Chengyu Zou
Qiaoyan Wu, Na Cui, Li Gao, Zhihui Lu, Xiang Ao, Rui Pang, Xingyan Li, Heling Pan, Daichao Xu, Peiying Li, Junying Yuan, Chengyu Zou
View: Text | PDF
Research In-Press Preview Autoimmunity Cell biology

Enhancing Treg persistence by inhibiting necroptosis restrains autoimmune pathology

Abstract

Regulatory T (Treg) cells 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 cell death, thereby compromising Treg functional persistence under inflammatory conditions. We further demonstrate that Treg cells in both a mouse model of MS and patients with MS exhibit a preferential susceptibility to RIPK1 kinase-dependent necroptosis. Mechanistically, a FOXP3-driven low-glucose metabolic program renders Treg cells intrinsically susceptible to necroptosis by limiting O-GlcNAc modification on RIPK1. This vulnerability is not shared by conventional T cells under comparable inflammatory conditions. Finally, in combined with adoptive Treg cell transfer, we show that selective inhibition of necroptosis in Treg cells enhances 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 Treg cells for the treatment of autoimmune diseases.

Authors

Qiaoyan Wu, Na Cui, Li Gao, Zhihui Lu, Xiang Ao, Rui Pang, Xingyan Li, Heling Pan, Daichao Xu, Peiying Li, Junying Yuan, Chengyu Zou

×
Problems with a PDF?

This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.

Having trouble reading a PDF?

PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.

Having trouble saving a PDF?

Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.

Having trouble printing a PDF?

  1. Try printing one page at a time or to a newer printer.
  2. Try saving the file to disk before printing rather than opening it "on the fly." This requires that you configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can usually be done in the "Helper Applications" options.
  3. Make sure you are using the latest version of Adobe's Acrobat Reader.

- Download (14.23 MB)

Advertisement