Microglial A20 Protects the Brain from CD8 T-Cell-Mediated Immunopathology
Alma Nazlie Mohebiany,
Nishada Shakunty Ramphal,
Khalad Karram,
Giovanni Di Liberto,
Tanja Novkovic,
Matthias Klein,
Federico Marini,
Mario Kreutzfeldt,
Franziska Härtner,
Sonja Maria Lacher,
Tobias Bopp,
Thomas Mittmann,
Doron Merkler,
Ari Waisman
Affiliations
Alma Nazlie Mohebiany
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany
Nishada Shakunty Ramphal
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany
Khalad Karram
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany
Giovanni Di Liberto
Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland
Tanja Novkovic
Institute for Physiology, University Medical Center, Johannes Gutenberg University of Mainz, 55131 Mainz, Germany
Matthias Klein
Institute for Immunology, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany
Federico Marini
Institute for Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany
Mario Kreutzfeldt
Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland
Franziska Härtner
Institute for Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany
Sonja Maria Lacher
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany
Tobias Bopp
Institute for Immunology, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany
Thomas Mittmann
Institute for Physiology, University Medical Center, Johannes Gutenberg University of Mainz, 55131 Mainz, Germany
Doron Merkler
Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland; Division of Clinical Pathology, Geneva University Hospital, 1211 Geneva, Switzerland
Ari Waisman
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany; Corresponding author
Summary: Tumor-necrosis-factor-alpha-induced protein 3 (TNFAIP3), or A20, is a ubiquitin-modifying protein and negative regulator of canonical nuclear factor κB (NF-κB) signaling. Several single-nucleotide polymorphisms in TNFAIP3 are associated with autoimmune diseases, suggesting a role in tissue inflammation. While the role of A20 in peripheral immune cells has been well investigated, less is known about its role in the central nervous system (CNS). Here, we show that microglial A20 is crucial for maintaining brain homeostasis. Without microglial A20, CD8+ T cells spontaneously infiltrate the CNS and acquire a viral response signature. The combination of infiltrating CD8+ T cells and activated A20-deficient microglia leads to an increase in VGLUT1+ terminals and frequency of spontaneous excitatory currents. Ultimately, A20-deficient microglia upregulate genes associated with the antiviral response and neurodegenerative diseases. Together, our data suggest that microglial A20 acts as a sensor for viral infection and a master regulator of CNS homeostasis. : A20, as a negative regulator of NF-κB signaling, plays an important role in regulating inflammation. Mohebiany et al. find that A20 in microglia plays a critical role in maintaining CNS homeostasis. When microglia lack A20, immune cells infiltrate the CNS, leading to alterations in microglial structure and neuronal activity. Keywords: microglia, neuroinflammation, CD8 T cells, A20, NF-κB
