Ribosome-Targeting Antibiotics Impair T Cell Effector Function and Ameliorate Autoimmunity by Blocking Mitochondrial Protein Synthesis

verfasst von

Luís Almeida, Ayesha Dhillon-LaBrooy, Carla N. Castro, Nigatu Adossa, Guilhermina M. Carriche, Melanie Guderian, Saskia Lippens, Sven Dennerlein, Christina Hesse, Bart N. Lambrecht, Luciana Berod, Leif Schauser, Bruce R. Blazar, Markus Kalesse, Rolf Müller, Luís F. Moita, Tim Sparwasser

Abstract

While antibiotics are intended to specifically target bacteria, most are known to affect host cell physiology. In addition, some antibiotic classes are reported as immunosuppressive for reasons that remain unclear. Here, we show that Linezolid, a ribosomal-targeting antibiotic (RAbo), effectively blocked the course of a T cell-mediated autoimmune disease. Linezolid and other RAbos were strong inhibitors of T helper-17 cell effector function in vitro, showing that this effect was independent of their antibiotic activity. Perturbing mitochondrial translation in differentiating T cells, either with RAbos or through the inhibition of mitochondrial elongation factor G1 (mEF-G1) progressively compromised the integrity of the electron transport chain. Ultimately, this led to deficient oxidative phosphorylation, diminishing nicotinamide adenine dinucleotide concentrations and impairing cytokine production in differentiating T cells. In accordance, mice lacking mEF-G1 in T cells were protected from experimental autoimmune encephalomyelitis, demonstrating that this pathway is crucial in maintaining T cell function and pathogenicity.

Organisationseinheit(en)

Institut für Organische Chemie

Externe Organisation(en)

TWINCORE Zentrum für Experimentelle und Klinische Infektionsforschung GmbH
Johannes Gutenberg-Universität Mainz
Qiagen N.V.
University of Turku
VIB Center for Inflammation Research (IRC)
Georg-August-Universität Göttingen
Fraunhofer-Institut für Toxikologie und Experimentelle Medizin (ITEM)
Universiteit Gent
University of Minnesota
Helmholtz-Zentrum für Infektionsforschung GmbH (HZI)
Universität des Saarlandes
Instituto Gulbenkian de Ciencia

Typ

Artikel

Journal

IMMUNITY

Band

54

Seiten

68-83

ISSN

1074-7613

Publikationsdatum

12.01.2021

Publikationsstatus

Veröffentlicht

Peer-reviewed

Ja

ASJC Scopus Sachgebiete

Immunologie und Allergologie, Immunologie, Infektionskrankheiten

Ziele für nachhaltige Entwicklung

SDG 3 – Gute Gesundheit und Wohlergehen

Elektronische Version(en)

https://doi.org/10.1016/j.immuni.2020.11.001 (Zugang: Offen)