TY - JOUR

T1 - Ribosome-Targeting Antibiotics Impair T Cell Effector Function and Ameliorate Autoimmunity by Blocking Mitochondrial Protein Synthesis

AU - Almeida, Luís

AU - Dhillon-LaBrooy, Ayesha

AU - Castro, Carla N.

AU - Adossa, Nigatu

AU - Carriche, Guilhermina M.

AU - Guderian, Melanie

AU - Lippens, Saskia

AU - Dennerlein, Sven

AU - Hesse, Christina

AU - Lambrecht, Bart N.

AU - Berod, Luciana

AU - Schauser, Leif

AU - Blazar, Bruce R.

AU - Kalesse, Markus

AU - Müller, Rolf

AU - Moita, Luís F.

AU - Sparwasser, Tim

N1 - Funding Information: We thank all members of the Institute of Infection Immunology at TWINCORE for discussion and support. We would like to acknowledge the assistance of the Cell Sorting Core Facility of the Hannover Medical School supported in part by the Braukmann-Wittenberg-Herz-Stiftung and the Deutsche Forschungsgemeinschaft . We thank Heinrich Steinmetz from Helmholtz Center for Infection Research for providing Arg C, Peter Rehling from University Medical Center (Göttingen) for providing resources to conduct mitochondrial translation assays, and the Department of Prenatal Medicine and Midwifery of the Medical School Hannover (MHH) for providing human cord blood. We would also like to thank the Teichmann Lab at the Wellcome Trust Sanger Institute, Dora Pedroso at Instituto Gulbenkian de Ciência, and Karsten Hiller’s group at Technische Universität Braunschweig for technical support. This work was supported by grants from the Deutsche Forschungsgemeinschaft ( CRC156 ) to T.S.; A.D.-L. was supported by the Hannover School for Biomedical Drug Research (HSBDR) and L.A. has received funding from the European Union ’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 675395 . B.R.B was supported by the National Institutes of Health R01 HL56067 and R37 AI34495 . L.F.M. was supported by the European Commission Horizon 2020 ( ERC-2014-CoG 647888 - iPROTECTION).

PY - 2021/1/12

Y1 - 2021/1/12

N2 - 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.

AB - 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.

KW - antibiotics

KW - Argyrin

KW - autoimmunity

KW - elongation factor G1

KW - Linezolid

KW - mitochondria

KW - mitochondrial translation

KW - NAD+

KW - ribosome-targeting

KW - T cells

UR - http://www.scopus.com/inward/record.url?scp=85098970312&partnerID=8YFLogxK

U2 - 10.1016/j.immuni.2020.11.001

DO - 10.1016/j.immuni.2020.11.001

M3 - Article

C2 - 33238133

AN - SCOPUS:85098970312

VL - 54

SP - 68

EP - 83

JO - IMMUNITY

JF - IMMUNITY

SN - 1074-7613

IS - 1

ER -