The cytokine and costimulatory pathways involved in acute GVHD. Chemoradiotherapy used in conditioning liberates a number of DAMP and PAMP signals that contribute to hematopoietic and nonhematopoietic APC activation (antigen presentation, costimulation molecule expression, and cytokine secretion). Allogeneic peptides presented in MHC are recognized by the TCR on conventional donor T cells in conjunction with a suite of costimulatory molecules (CD40-CD40L, CD80/86-CD28, OX40L-OX40, ICOSL-ICOS) that together with appropriate cytokine signals (eg, IL-12, IL-6, IL-23) drives T-cell differentiation and their secretion of effector cytokines (eg, IFN-γ, IL-17, TNF, GM-CSF) that invoke local inflammation to mediate target tissue apoptosis directly and by recruitment of additional immune effector cells. The activation of Tregs involves MHC/peptide-TCR interactions, costimulatory and coinhibitory molecule engagement (eg, TIGIT and CTLA-4), and additional cytokine signals from IL-33 that enhance cytokine secretion mediating regulatory and repair function (eg, IL-10/TGF-β and amphiregulin, respectively). Over time, many of these coinhibitory molecules are expressed by conventional T effector cells.