Τίτλος:
Mitochondrial Oxidative Damage Underlies Regulatory T Cell Defects in Autoimmunity
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2020 Elsevier Inc.
Συγγραφείς:
Alissafi, T.
Kalafati, L.
Lazari, M.
Filia, A.
Kloukina, I.
Manifava, M.
Lim, J.-H.
Alexaki, V.I.
Ktistakis, N.T.
Doskas, T.
Garinis, G.A.
Chavakis, T.
Boumpas, D.T.
Verginis, P.
Περιοδικό:
Cell Metabolism
Λέξεις-κλειδιά:
reactive oxygen metabolite; transcription factor FOXP3, animal experiment; animal model; apoptosis; Article; autoimmune disease; autoimmunity; cell death; clinical article; controlled study; disorders of mitochondrial functions; DNA damage response; experimental allergic encephalitis; homeostasis; human; human cell; immunological tolerance; immunotherapy; in vitro study; in vivo study; lysosome; mitochondrial respiration; mitophagy; mouse; nonhuman; oxidative stress; oxygen consumption rate; priority journal; regulatory T lymphocyte; steady state; animal; autoimmunity; C57BL mouse; cell line; immunology; knockout mouse; mitochondrion; oxidation reduction reaction; regulatory T lymphocyte, Animals; Autoimmunity; Cell Line; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Oxidation-Reduction; T-Lymphocytes, Regulatory
DOI:
10.1016/j.cmet.2020.07.001
