Schematic overview of the cellular and molecular mediators, known and implicated, contributing to the continuum of aGVHD and cGVHD pathology. Both naive T cells (T_N) and their precursors (HSCs, common lymphoid progenitor [CLP]) contained within the stem cell graft contribute to cGVHD pathology. Mature donor T cells within the graft contribute to thymic destruction resulting in disrupted immune reconstitution. Thymic dysfunction favors the selection of autoreactive and alloreactive T cells polarized toward Th17/Tc17 lineages. Donor-derived DC APC function is corrupted during aGVHD, reducing their capacity to expand and maintain Tregs in the periphery. T-follicular helper cell (T_FH)-derived IL-21, together with elevated levels of BAFF, result in aberrant B-cell reconstitution favoring GC B-cell (GBC) expansion. Polyfunctional Th17/Tc17 cells migrate to target organs where secreted IL-17 may function as a chemokine for Ly6Clo monocytes. CSF-1 derived in part from Th17/Tc17 promotes the differentiation of Ly6Clo monocytes into tissue-resident macrophages (MΦ), which are polarized toward an M2 phenotype under the influence of multiple proinflammatory cytokines (GM-CSF, IL-22, IL-13, and IFNγ) produced by Th17/Tc17. Plasma cell–derived allo/autoantibodies (Ab) can bind to Fc receptors on macrophages, contributing to their polarization and promotion of TGFβ secretion, which promotes fibroblast activation and collagen production. Fc, receptor for immunoglobulins; T_allo, alloreactive T cell; T_EFF, effector T cell.