IL-4 downregulates BCL6 to promote memory B cell selection in germinal centers

Abstract Germinal center (GC)-derived memory B cells (MBCs) are critical for humoral immunity as they differentiate into protective antibody-secreting cells during re-infection. GC formation and cellular interactions within the GC have been studied in detail, yet the exact signals that allow for the selection and exit of MBCs are not understood. We show that IL-4 can trigger GC B cell selection and exit by inducing the negative autoregulation of BCL6, the primary GC transcription factor. High affinity/avidity GC B cells that secure additional help and upregulate MBC survival signals to replace the loss of BCL6 exit the GC as memory cells, whereas those that do not are primed for cell death. In this way, IL-4 signaling regulates selection and affinity maturation within the MBC pool.