Thioredoxin is a metabolic rheostat controlling regulatory B cells

Hannah F Bradford; Thomas C. R. McDonnell; Alexander Stewart; Andrew Skelton; Joseph Ng; Zara Baig; Franca Fraternali; Deborah Dunn-Walters; David A. Isenberg; Adnan R. Khan; Claudio Mauro; Claudia Mauri

doi:10.1038/s41590-024-01798-w

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Thioredoxin is a metabolic rheostat controlling regulatory B cells

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Thioredoxin is a metabolic rheostat controlling regulatory B cells

Hannah F Bradford, Thomas C. R. McDonnell, Alexander Stewart, Andrew Skelton, Joseph Ng, Zara Baig, Franca Fraternali, Deborah Dunn-Walters, David A. Isenberg, Adnan R. Khan, …

Nature Immunology, Vol.25, pp.873-885

05/2024

DOI: https://doi.org/10.1038/s41590-024-01798-w

Abstract

B cells

Autoimmunity

Biochemistry

Pathogenesis

Metabolic programming is important for B cell fate, but the bioenergetic requirement for regulatory B (B_reg) cell differentiation and function is unknown. Here we show that Breg cell differentiation, unlike non-B_reg cells, relies on mitochondrial electron transport and homeostatic levels of reactive oxygen species (ROS). Single-cell RNA sequencing analysis revealed that TXN, encoding the metabolic redox protein thioredoxin (Trx), is highly expressed by B_reg cells, unlike Trx inhibitor TXNIP which was downregulated. Pharmacological inhibition or gene silencing of TXN resulted in mitochondrial membrane depolarization and increased ROS levels, selectively suppressing B_reg cell differentiation and function while favoring pro-inflammatory B cell differentiation. Patients with systemic lupus erythematosus (SLE), characterized by B_reg cell deficiencies, present with B cell mitochondrial membrane depolarization, elevated ROS and fewer Trx⁺ B cells. Exogenous Trx stimulation restored B_reg cells and mitochondrial membrane polarization in SLE B cells to healthy B cell levels, indicating Trx insufficiency underlies B_reg cell impairment in patients with SLE.

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Title: Thioredoxin is a metabolic rheostat controlling regulatory B cells
Creators: Hannah F Bradford (Corresponding Author) - University College London
Thomas C. R. McDonnell (Author) - University College London
Alexander Stewart (Author) - University of Surrey, School of Biosciences
Andrew Skelton (Author) - UCB Pharma
Joseph Ng (Author) - University College London
Zara Baig (Author) - University College London
Franca Fraternali (Author) - University College London
Deborah Dunn-Walters (Author) - University of Surrey, School of Biosciences
David A. Isenberg (Author) - University College London
Adnan R. Khan (Author) - UCB Pharma
Claudio Mauro (Author) - University of Birmingham
Claudia Mauri (Corresponding Author) - University College London
Publication Details: Nature Immunology, Vol.25, pp.873-885
Publisher: Nature Research
Date published: 05/2024
Date accepted: 28/02/2024
Grants: MR/L01257X/2, Medical Research Council (United Kingdom, London) - MRC
Mapping Antibody Class Switching Mechanisms and Function (MACSMAF) , BB/T002212/1 , Biotechnology and Biological Sciences Research Council (United Kingdom, Swindon) - BBSRC
Program grant, 21140, Versus Arthritis (United Kingdom, Chesterfield)
PhD Studentship, BB/P504725/1, UCB Pharma (United Kingdom, Slough)
Medical Research Foundation Fellowship, MRF-057-0004-RG-MCDO-C0800, Medical Research Foundation (United Kingdom, London)
Senior Fellowship, ShS/SRF/22977, Versus Arthritis (United Kingdom, Chesterfield)
Senior Basic Science Research Fellowship, FS/SBSRF/22/31031, British Heart Foundation (United Kingdom, London) - BHF
Grant note: This work is funded by a Versus Arthritis UK program grant (no. 21140), awarded to C. Mauri; a UCB BIOPHARMA SPRL/BBSRC PhD Studentship (grant no. BB/P504725/1) awarded to C. Mauri to fund H.F.B.; an MRC grant (no. MR/L01257X/2) awarded to D.D.-W.; and a BBSRC grant (no. BB/T002212/1) awarded to C. Mauri, F.F. and D.D.-W. T.C.R.M. is funded by a Medical Research Foundation Fellowship (grant no. MRF-057-0004-RG-MCDO-C0800) and a Versus Arthritis Senior Fellowship (grant no. ShS/SRF/22977). C. Mauro is funded by a British Heart Foundation Senior Basic Science Research Fellowship (grant no. FS/SBSRF/22/31031).
Identifiers: 99903366602346
Copyright: Copyright © 2024, The Author(s). Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Academic Unit: School of Biosciences
Language: English
Resource Type: Journal article
Data Access Statement: Human scRNA-seq data have been deposited in ArrayExpress under accession code E-MTAB-13872. For scRNA-seq transcriptomic analysis, the GRCh38 reference genome was downloaded using the Bioconductor annotation package BSgenome.Hsapiens.NCBI.GRCh38. All other data are available in the article and Supplementary Information or from the corresponding authors upon reasonable request.

Thioredoxin is a metabolic rheostat controlling regulatory B cells

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