Model for a NOTCH2-BCR axis in the generation of pathogenic B cells in cGVHD. (A) Reduced activation threshold response to antigen and to NOTCH ligand. High BAFF levels in the cGVHD setting leads to the preferential survival of B cells with MZ-like properties. These B cells are driven by an abnormally low ratio of IRF4 to IRF8, and are dependent on NOTCH2 activation of target genes. BCR-NOTCH2 synergy in these B cells leads to pathogenic Allo-Ab production. (B) ATRA exposure normalizes the phenotype of cGVHD B cells by increasing the ratio of IRF4 to IRF8, eliminating NOTCH2 dependence. This in turn leads to enhanced expression of PAX5 and TLR9, a genetic profile associated with mature follicular B cells capable of producing protective Ab against bacteria and viruses, as well as to vaccines. Importantly, these B cells attain functional memory essential for long-term humoral immunity.