Journal Article

Second signals rescue B cells from activation-induced mitochondrial dysfunction and death

Kabat, Juraj, Smelkinson, Margery, Sack, Michael N., Pierce, Susan K., Akkaya, Munir, Pena, Mirna, Miozzo, Pietro, Traba, Javier, Dahlstrom, Eric, Dorward, David W., Roesler, Alexander S., Akkaya, Billur, Skinner, Jeff, Theall, Brandon P., Sohn, Haewon

2018

Overview

B cells are activated by two temporally distinct signals, the first provided by the binding of antigen to the B cell antigen receptor (BCR), and the second provided by helper T cells. Here we found that B cells responded to antigen by rapidly increasing their metabolic activity, including both oxidative phosphorylation and glycolysis. In the absence of a second signal, B cells progressively lost mitochondrial function and glycolytic capacity, which led to apoptosis. Mitochondrial dysfunction was a result of the gradual accumulation of intracellular calcium through calcium response–activated calcium channels that, for approximately 9 h after the binding of B cell antigens, was preventable by either helper T cells or signaling via the receptor TLR9. Thus, BCR signaling seems to activate a metabolic program that imposes a limited time frame during which B cells either receive a second signal and survive or are eliminated. B cells need at least two signals to terminally differentiate into antibody-secreting cells. Pierce and colleagues show that persistent exposure to antigen in the absence of T cell help or ‘pathogen pattern motifs’ leads to B cell death via a calcium-dependent ‘metabolic timer’.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/2152 / 631/80/82/23 / Animals / Antibodies / Antigens / Apoptosis / B cells / B-cell receptor / B-Lymphocytes - physiology / Biomedical and Life Sciences / Biomedicine / Calcium (intracellular) / Calcium - metabolism / Calcium channels / Calcium Channels - metabolism / Cell activation / Cell death / Cytokines - metabolism / Glucose metabolism / Glycolysis / Immunology / Infectious Diseases / Lymphocyte Activation / Lymphocytes B / Lymphocytes T / Metabolism / Mice / Mice, Inbred C57BL / Mice, Knockout / Mice, Transgenic / Mitochondria / Mitochondria - metabolism / NIH 3T3 Cells / Oxidative Phosphorylation / Phosphorylation / Receptors, Antigen, B-Cell - genetics / Receptors, Antigen, B-Cell - metabolism / Signal Transduction / T cell receptors / T cells / T-Lymphocytes, Helper-Inducer - immunology / TLR9 protein / Toll-Like Receptor 9 - genetics / Toll-Like Receptor 9 - metabolism / Toll-like receptors