Metabolic Reprogramming Commits Differentiation of Human CD27 + IgD + B Cells to Plasmablasts or CD27 - IgD - Cells

• Published in: The Journal of immunology (1950) Vol. 199; no. 2; pp. 425 - 434
• Main Authors: Torigoe, Masataka, Iwata, Shigeru, Nakayamada, Shingo, Sakata, Kei, Zhang, Mingzeng, Hajime, Maiko, Miyazaki, Yusuke, Narisawa, Manabu, Ishii, Koji, Shibata, Hirotaka, Tanaka, Yoshiya
• Format: Journal Article
• Language: English
• Published: United States American Association of Immunologists 15.07.2017
• Subjects: Adolescent; Adult; Aged; AMP; AMP-activated protein kinase; Autoimmune diseases; B-Lymphocyte Subsets - immunology; B-Lymphocyte Subsets - metabolism; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; CD19 antigen; CD27 antigen; Cell activation; Cell Differentiation - drug effects; Female; Flow Cytometry; Glycolysis; Humans; Immunoglobulin D; Immunoglobulin D - deficiency; Immunoglobulin D - genetics; Immunoglobulin D - immunology; Immunologic Memory; Immunological memory; Immunophenotyping; Interferon; Interferon-alpha - immunology; Kinases; Lactic acid; Lactic Acid - biosynthesis; Lupus Erythematosus, Systemic - immunology; Lymphocyte receptors; Lymphocytes B; Male; Mechanistic Target of Rapamycin Complex 1; Memory cells; Metabolic Networks and Pathways - genetics; Metabolism; Middle Aged; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Oligodeoxyribonucleotides - immunology; Pathogenesis; Plasma Cells - immunology; Plasma Cells - metabolism; Plasma Cells - physiology; Protein Kinases - metabolism; Rapamycin; Systemic lupus erythematosus; TLR9 protein; Toll-Like Receptor 9 - immunology; Toll-like receptors; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Tumor Necrosis Factor Receptor Superfamily, Member 7 - genetics; Tumor Necrosis Factor Receptor Superfamily, Member 7 - immunology; Young Adult
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1601908

B cells play a crucial role in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE). However, the relevance of the metabolic pathway in the differentiation of human B cell subsets remains unknown. In this article, we show that the combination of CpG/TLR9 and IFN-α markedly induced the differentiation of CD27 IgD unswitched memory B cells into CD27 CD38 plasmablasts. The response was accompanied by mammalian target of rapamycin complex 1 (mTORC1) activation and increased lactate production, indicating a shift to glycolysis. However, CpG alone induced the differentiation of unswitched memory B cells into CD27 IgD memory B cells with high cytokine production, but such differentiation was suppressed by IFN-α. AMP-activated protein kinase activation enhanced the differentiation to CD27 IgD B cells, but it attenuated mTORC1 activation and differentiation into plasmablasts. High mTORC1 activation was noted in CD19 B cells of patients with SLE and correlated with plasmablast differentiation and disease activity. Taken together, differential metabolic reprogramming commits the differentiation of human unswitched memory B cells into plasmablasts (the combination of CpG and IFN-α amplifies mTORC1-glycolysis pathways) or CD27 IgD memory B cells (CpG alone amplifies the AMP-activated protein kinase pathway). The former metabolic pathway may play a pivotal role in SLE.