Alloantigen presentation in acute GVHD. After conditioning, antigen presentation is augmented in recipient hematopoietic APCs (eg, DCs) and nonhematopoietic APCs (eg, IECs in the ileum) via microbiota-driven cytokine signals (IL-12 from macrophages and interferon-γ [IFN-γ] from type-1 innate lymphoid cells [ILC1] and T cells). After transplantation, naïve donor T cells encounter alloantigen in the lymphoid organs (primarily presented by hematopoietic APCs) and in the GI tract (presented by hematopoietic APCs and nonhematopoietic APCs, including IECs) and undergo pathogenic (Th1/Th17) differentiation to initiate target tissue damage (GVHD). After engraftment, and in the presence of disrupted barrier function in the colon mediated by GVHD, donor colonic DCs expand and present large amounts of locally acquired alloantigen. These donor DCs migrate from the colon to the mesenteric lymph node under the influence of CCR7 and present alloantigen to new donor T cells, which undergo activation and Th1/Th17 differentiation under the influence of IL-12/IL-6. Finally, donor T cells are imprinted with α4β7 integrins, which guide their migration to the GI tract to perpetuate severe acute GVHD in a feed-forward cascade. Adapted from Koyama and Hill¹¹  and Koyama et al³⁸  with permission.