Mitochondrial Oxidative Damage Underlies Regulatory T Cell Defects in Autoimmunity

Research output: Contribution to journalResearch articleContributedpeer-review



Regulatory T cells (Tregs) are vital for the maintenance of immune homeostasis, while their dysfunction constitutes a cardinal feature of autoimmunity. Under steady-state conditions, mitochondrial metabolism is critical for Treg function; however, the metabolic adaptations of Tregs during autoimmunity are ill-defined. Herein, we report that elevated mitochondrial oxidative stress and a robust DNA damage response (DDR) associated with cell death occur in Tregs in individuals with autoimmunity. In an experimental autoimmune encephalitis (EAE) mouse model of autoimmunity, we found a Treg dysfunction recapitulating the features of autoimmune Tregs with a prominent mtROS signature. Scavenging of mtROS in Tregs of EAE mice reversed the DDR and prevented Treg death, while attenuating the Th1 and Th17 autoimmune responses. These findings highlight an unrecognized role of mitochondrial oxidative stress in defining Treg fate during autoimmunity, which may facilitate the design of novel immunotherapies for diseases with disturbed immune tolerance. Herein, Alissafi et al. reveal that in Tregs during autoimmunity there is elevated mitochondrial oxidative stress, which induces a DNA damage response and cell death. Using a mouse model, they show that mitochondrial ROS scavenging in Tregs ameliorates autoimmune responses. These findings define new Treg checkpoints in autoimmune diseases.


Original languageEnglish
Pages (from-to)591-604.e7
JournalCell metabolism
Issue number4
Publication statusPublished - 6 Oct 2020

External IDs

PubMed 32738205



  • autoimmunity, DNA damage response, lysosome, metabolism, mitochondrial oxidative stress, regulatory T cell