# Thioredoxin is a metabolic rheostat controlling regulatory B cells

## TL;DR

Thioredoxin helps control regulatory B cells by managing mitochondrial energy and reactive oxygen species, which is important in diseases like lupus.

## Contribution

The study identifies thioredoxin as a key metabolic regulator of regulatory B cell function and its role in systemic lupus erythematosus.

## Key findings

- Breg cell differentiation depends on mitochondrial electron transport and ROS homeostasis.
- Thioredoxin is highly expressed in Breg cells and its inhibition suppresses their function.
- Exogenous Trx restores Breg cell function in SLE patients by normalizing mitochondrial and ROS levels.

## Abstract

Metabolic programming is important for B cell fate, but the bioenergetic requirement for regulatory B (Breg) cell differentiation and function is unknown. Here we show that Breg cell differentiation, unlike non-Breg 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 Breg 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 Breg cell differentiation and function while favoring pro-inflammatory B cell differentiation. Patients with systemic lupus erythematosus (SLE), characterized by Breg cell deficiencies, present with B cell mitochondrial membrane depolarization, elevated ROS and fewer Trx+ B cells. Exogenous Trx stimulation restored Breg cells and mitochondrial membrane polarization in SLE B cells to healthy B cell levels, indicating Trx insufficiency underlies Breg cell impairment in patients with SLE.

Here the authors show a mechanism by which mitochondrial electron transport and ROS contribute to the differentiation and function of regulatory B cells in the context of systemic lupus erythematosus.