Extended Data Fig. 9: The IRF4 imprinting model and implications for the B cell response.

a, The basis of history-imprinted, epigenetically recorded PC differentiation potential of individual B cells. The history of stimulation is read by IRF4 in that stimulation by antigen, T cell help, innate stimuli and cytokines promotes IRF4 expression in a dose-dependent manner. IRF4 writes this history epigenetically by opening chromatins at ISRE-containing loci that specify the PC differentiation program, including the Prdm1 locus. Chromatin accessibilities at GC-sustaining Bach2 locus and the locus of its upstream regulator Pax5 (not depicted) are gradually decreased. As a result of continuous action of IRF4, the relative strength of BLIMP-1 over BACH2 is increased. b, A proposed model of the B cell response dictated by the stimulation history-imprinted, epigenetically recorded PC differentiation potential. Shades of the blue color represent the degree to which cells have undergone IRF4 imprinting, the remaining distance to the PC state on the naïve-to-PC differentiation axis, or the potential to become plasma cells upon next episode of stimulation. Stronger stimulation of naïve B cells may result in direct generation of plasma cells, while weaker stimulation permits GC formation. Memory B cells that have undergone less IRF4 imprinting tend to re-participate in the GC reaction while those that have undergone stronger IRF4 imprinting tend to produce plasma cells. GC B cells that have undergone less IRF4 imprinting are more likely to produce memory B cells while those that have undergone more are to produce plasma cells. As a consequence, output from GCs in the early response contain more memory B cells, while output from GCs in the late primary response tend to contain more plasma cells. From secondary GCs produced by reactivated memory B cells, plasma cell output dominates. Created with BioRender.com.