Early acute GI GVHD. At steady state, ISCs and Paneth cells are adjacent at the base of the intestinal crypts. Homeostasis is maintained, in part, by large numbers of commensal bacteria that stimulate IL-22 production by ILC3s. During GVHD, activated donor T cells recognize histocompatibility antigens on both hematopoietic (HP) and nonhematopoietic antigen-presenting cells (APCs). Activated APCs and T cells trigger the release of alarmins, such as IL-33, that bind to its receptor ST2; soluble ST2 (both bound to IL-33 and unbound) can enter the villus capillaries. Activated donor T cells destroy ILC3s, Paneth cells, and ISCs, releasing REG3A that was stored in the mucus and Paneth cells into the bloodstream as the epithelial barrier is breached.