CHK1 dosage in germinal center B cells controls humoral immunity

Cell Death Differ. 2019 Dec;26(12):2551-2567. doi: 10.1038/s41418-019-0318-5. Epub 2019 Mar 20.


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.

MeSH terms

  • Animals
  • B-Lymphocytes / immunology*
  • Cell Survival / genetics
  • Cells, Cultured
  • Checkpoint Kinase 1 / genetics
  • Checkpoint Kinase 1 / immunology*
  • DNA Damage
  • Female
  • Germinal Center / immunology*
  • Immunity, Humoral / genetics
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred C57BL


  • Checkpoint Kinase 1
  • Chek1 protein, mouse