Working model for the role of soluble BAFF in promotion of and BCR-activation of pathogenic B cells in chronic GVHD. In our paper, we now demonstrate a mechanistic role for BAFF in chronic GVHD (cGVHD) using a mouse model. Our data afford the working model depicted here. BAFF levels and BAFF production are significantly increased in cGVHD mice. Recipient Fibroblastic Reticular Cells (FRCs) and Donor T Follicular Helper (TFH) Cells are likely cellular sources of this pathologic BAFF. Excess BAFF in cGVHD promotes survival of subsets of activated B cells. In turn, BAFF and alloantigen work together to augment B Cell Receptor (BCR) activation, in part, by increasing co-stimulatory NOTCH2 on B cells in mice that go on to develop cGVHD manifestations. At the molecular level, these B cells exposed to a high BAFF, NOTCH ligand and alloantigen environment are able to maintain SYK protein even after BCR re-engagement, perpetuating a BCR-responsive B cell compartment in cGVHD.