Mechanisms of SR-GVHD. (A) Cellular mechanisms. Steroids regulate the majority of Th1 responses but can paradoxically increase Th2 and pathogenic Th17-mediated immune responses that may promote GVHD. The role of steroids in CD8⁺ T cells is uncertain. The combination of steroids with calcineurin inhibitor (CNI) may unintentionally blunt induction of Tregs based on their requirement for IL-2 resulting in loss of peripheral tolerance. (B) Molecular mechanisms. Steroids repress expression of TFs necessary for production of proinflammatory cytokines (IL-6, TNFα). In addition, steroids promote induction of regulatory cell subsets, such as CD103⁺ DCs and M2 MFs that induce immune tolerance. In refractory disease, long-term use of steroids may paradoxically increase expression of TLRs and NLRP3 that perpetuate inflammation. (C) Target tissue–intrinsic mechanisms. In the GI tract, steroids can impede the reparative processes of the host following T-cell–mediated injury that is associated with loss of Paneth cells, ISCs, and immune-regulatory proteins (α-1-antitrypsin [AAT]). Limited tissue regeneration from long-term suppression of inflammation with ongoing mucosal barrier injury is associated with alterations in the intestinal microbiome and metabolome. Dysbiosis results in loss of protective metabolites (butyrate). Ongoing inflammation can eventually stimulate APCs to increase production of proinflammatory cytokines that further damage host tissue. AP-1, activator protein 1; GCR, glucocorticoid receptor; ROS, reactive oxygen species; Tc, cytotoxic T cell; TCR, T-cell receptor.