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Cell Death Differ. 2019 Mar 20. doi: 10.1038/s41418-019-0318-5. [Epub ahead of print]

CHK1 dosage in germinal center B cells controls humoral immunity.

Author information

1
Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, 6020, Austria.
2
Division of Translational Cell Genetics, Department for Pharmacology and Genetics, Medical University of Innsbruck, Innsbruck, 6020, Austria.
3
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, 1090, Austria.
4
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, 1090, Austria.
5
Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, 6020, Austria. verena.labi@i-med.ac.at.

Abstract

Germinal center (GC) B cells are among the fastest replicating cells in our body, dividing every 4-8 h. DNA replication errors are intrinsically toxic to cells. How GC B cells exert control over the DNA damage response while introducing mutations in their antibody genes is poorly understood. Here, we show that the DNA damage response regulator Checkpoint kinase 1 (CHK1) is essential for GC B cell survival. Remarkably, effective antibody-mediated immunity relies on optimal CHK1 dosage. Chemical CHK1 inhibition or loss of one Chk1 allele impairs the survival of class-switched cells and curbs the amplitude of antibody production. Mechanistically, active B cell receptor signaling wires the outcome of CHK1-inhibition towards BIM-dependent apoptosis, whereas T cell help favors temporary cell cycle arrest. Our results predict that therapeutic CHK1 inhibition in cancer patients may prove potent in killing B cell lymphoma and leukemia cells addicted to B cell receptor signaling, but will most likely dampen humoral immunity.

PMID:
30894677
DOI:
10.1038/s41418-019-0318-5

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