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Abstract
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 B reg 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.
Original language | English |
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Number of pages | 31 |
Journal | Nature Immunology |
Early online date | 29 Mar 2024 |
DOIs | |
Publication status | E-pub ahead of print - 29 Mar 2024 |
Bibliographical 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).Fingerprint
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Investigating and exploiting lactate signalling in athero-immunometabolism
1/02/23 → 31/01/28
Project: Research