Bach2 repression of CD36 regulates lipid-metabolism-linked effector functions in follicular B cells

• Published in: Cell reports (Cambridge) 2024-11, Vol.43 (11), p.114878, Article 114878
• Main Authors: Jang, Eunkyeong, Kim, ChangYeon, Noh, Jeonghyun, Yi, Hansol, Jo, Sungsin, Park, Jin-Sil, Hwang, Woochang, Cha, Ji-Young, Cho, Mi-La, Kim, Tae-Hwan, Youn, Jeehee
• Format: Article
• Language: English
• Subjects: Animals; B cells; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Bach2; Basic-Leucine Zipper Transcription Factors - metabolism; CD36; CD36 Antigens - metabolism; Cell Differentiation; CP: Immunology; CP: Metabolism; Fatty Acids - metabolism; follicular B cells; IL-6; Interleukin-6 - metabolism; Lipid Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxidative Stress
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114878

The transcription repressor Bach2 plays a crucial role in shaping humoral immunity, but its cell-autonomous function remains elusive. Here, we reveal the mechanism by which Bach2 regulates effector cell maturation in peripheral B cells. In response to Toll-like receptor (TLR) agonists, Bach2 deficiency promotes the differentiation of follicular, but not marginal zone, B cells into effector cells, producing interleukin (IL)-6 and antibodies. This phenomenon is associated with changes in lipid metabolism, such as increases in CD36 expression, lipid influx, and fatty acid oxidation. Consistent with this, Bach2-deficient B cells exhibit elevated levels of mitochondrial oxidative stress, lipid peroxidation, and p38 activation. Mechanistically, Bach2 acts as a repressor of Cd36, and inhibition of CD36 or fatty acid oxidation reduces the differentiation of naive B cells into IL-6- and antibody-secreting cells. These results indicate Bach2 as a key metabolic checkpoint regulator crucial for maintaining a functionally quiescent state of follicular B cells. [Display omitted] •Bach2 deficiency drives follicular B cells to give rise to IL-6- and Ab-producing cells•Bach2 regulates B cell lipid metabolism by acting as a transcriptional repressor of CD36•Changes in CD36-mediated lipid metabolism affect follicular B cell maturation•Bach2 is a key metabolic factor crucial for regulating follicular B cell fates Jang et al. report that Bach2 regulates the differentiation of follicular B cells into effector cells by altering CD36-mediated lipid metabolism. They identify Bach2 as a metabolic regulator crucial for determining B cell fates. This study defines a fundamental connection between the metabolic program and functions in B cells.