Antigen-affinity controls pre-germinal center B cell selection by promoting Mcl-1 induction through BAFF receptor signaling

Sci Rep. 2016 Oct 20;6:35673. doi: 10.1038/srep35673.

Abstract

Upon antigen encounter, the responsive B cell pool undergoes stringent selection which eliminates cells with low B cell receptor (BCR) affinity. Already before formation of the germinal center, activated B cells of low-affinity are negatively selected in a process that is molecularly not well understood. In this study, we investigated the mechanism behind pre-GC affinity-mediated B cell selection. We applied affinity mutants of HEL antigen and found that rapidly after activation B cells become highly dependent on the cytokine BAFF. Moreover, expression of BAFF receptor CD268 is regulated in a BCR-affinity dependent fashion. High affinity responses via BAFF correlated with PI3K activation, which controlled expression of the pro-survival protein Mcl-1, and thereby increased survival. In the presence of excess BAFF, or in absence of the Mcl-1 antagonist Noxa, more low-affinity B cells survived the first two days after antigen encounter. This resulted in increased numbers of antigen-specific B cells of low affinity upon immunization and reduced the overall affinity of cells that contributed to the germinal center reaction. Our findings elucidate a crucial molecular pathway of B cell selection in the earliest phases of activation by identifying a novel link between BCR affinity and BAFF-R signaling towards Mcl-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens / immunology*
  • B-Cell Activating Factor / metabolism
  • B-Cell Activation Factor Receptor / metabolism*
  • B-Lymphocytes / immunology*
  • Cell Survival
  • Mice, Inbred C57BL
  • Muramidase / immunology
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Signal Transduction*

Substances

  • Antigens
  • B-Cell Activating Factor
  • B-Cell Activation Factor Receptor
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Tnfsf13b protein, mouse
  • Phosphatidylinositol 3-Kinases
  • hen egg lysozyme
  • Muramidase