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

authored by

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.

Organisation(s)

Institute of Organic Chemistry

External Organisation(s)

TWINCORE Zentrum für Experimentelle und Klinische Infektionsforschung GmbH
Johannes Gutenberg University Mainz
Qiagen N.V.
University of Turku
VIB Center for Inflammation Research (IRC)
University of Göttingen
Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM)
Ghent University
University of Minnesota
Helmholtz Centre for Infection Research (HZI)
Saarland University
Instituto Gulbenkian de Ciencia

Type

Article

Journal

IMMUNITY

Volume

54

Pages

68-83

ISSN

1074-7613

Publication date

12.01.2021

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

Immunology and Allergy, Immunology, Infectious Diseases

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

https://doi.org/10.1016/j.immuni.2020.11.001 (Access: Open)