Posttranslational modification with SUMO is known to regulate the activity of transcription factors, but how SUMOylation of individual proteins might influence immunity is largely unexplored. The NFAT transcription factors play an essential role in antigen receptor-mediated gene regulation. SUMOylation of NFATc1 represses IL-2 in vitro, but its role in T cell–mediated immune responses in vivo is unclear. To this end, we generated a novel transgenic mouse in which SUMO modification of NFATc1 is prevented. Avoidance of NFATc1 SUMOylation ameliorated experimental autoimmune encephalomyelitis as well as graft-versus-host disease. Elevated IL-2 production in T cells promoted T reg expansion and suppressed autoreactive or alloreactive immune responses. Mechanistically, increased IL-2 secretion counteracted IL-17 and IFN-γ expression through STAT5 and Blimp-1 induction. Then, Blimp-1 repressed IL-2 itself, as well as the induced, proliferation-associated survival factor Bcl2A1. Collectively, these data demonstrate that prevention of NFATc1 SUMOylation fine-tunes T cell responses toward lasting tolerance. Thus, targeting NFATc1 SUMOylation presents a novel and promising strategy to treat T cell–mediated inflammatory diseases.
Lack of NFATc1 SUMOylation prevents autoimmunity and alloreactivity
Disclosures: L. Dietz reported other funding from Pfizer Pharma GmbH outside the submitted work. No other disclosures were reported.
M. Vaeth’s present address is Max Planck Research Group for Systems Immunology, University of Wuerzburg, Wuerzburg, Germany. S.D. Vallabhapurapu’s present address is Division of Hematology and Oncology, Dept. of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH. A. Mottok’s present address is Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany. M. Buttmann’s present address is Caritas-Krankenhaus Bad Mergentheim, Bad Mergentheim, Germany.
- Views Icon Views
- Share Icon Share
- Search Site
Yin Xiao, Musga Qureischi, Lena Dietz, Martin Vaeth, Subrahmanya D. Vallabhapurapu, Stefan Klein-Hessling, Matthias Klein, Chunguang Liang, Anika König, Edgar Serfling, Anja Mottok, Tobias Bopp, Andreas Rosenwald, Mathias Buttmann, Ingolf Berberich, Andreas Beilhack, Friederike Berberich-Siebelt; Lack of NFATc1 SUMOylation prevents autoimmunity and alloreactivity. J Exp Med 4 January 2021; 218 (1): e20181853. doi: https://doi.org/10.1084/jem.20181853
Download citation file: