The initiation and amplification of GVHD by alloantigen presentation. Naive donor T cells contaminating the stem cell graft migrate into recipient lymph nodes and/or GVHD target organs, particularly the gastrointestinal (GI) tract. They encounter recipient alloantigen presented by recipient APCs in the lymph nodes and/or by recipient nonhematopoietic APCs, including those in target tissue (eg, fibroblasts, epithelial cells). The latter obtain functional antigen presentation capacity following tissue damage induced by chemoradiotherapy during conditioning and cytokines generated following donor T cell activation. Hereafter, donor T cells proliferate and differentiate into Th1 and Th17 cells and induce GVHD in the target tissues, particularly the GI tract. Tissue damage within the colon at this point allows microbiome-derived damage-associated molecular pattern/pathogen-associated molecular pattern (DAMP/PAMP) signals to expand and activate donor CD103⁺ DCs in situ, which subsequently migrate into the mesenteric lymph node, under the influence of CCR7. Within the mesenteric lymph node, these donor DCs secrete IL-12 and present alloantigen to donor T cells to further drive pathological Th1 and Th17 differentiation while imprinting gut-homing α4β7 integrins, permissive of massive secondary migration into the gut, resulting in fulminant disease. Schematic highly modified from Koyama et al⁴²  with permission.