Role of DCs in the pathogenesis of GVHD. (A) Recipient pretransplant conditioning results in target organ tissue damage, leading to the so-called “cytokine storm,” a progressive amplification of proinflammatory cytokine production and immune activation as inflammatory cytokines feed forward unabated. IL-1β, IL-6, and TNF-α are particularly implicated in this process. In addition to proinflammatory cytokines, conditioning-released damage-associated molecular patterns (DAMPS) and translocation of lipopolysaccharide in the intestine also lead to the activation of host and subsequently donor DCs, including epidermal LCs and dermal DCs in the skin. Mature DCs up-regulate MHC, costimulatory, and intercellular adhesion molecule expression. (B) DCs present host allo-Ag to donor T cells. Host DCs resistant to conditioning present alloAg via the direct pathway, whereas transplanted donor DCs present processed alloAg peptides on MHC syngeneic with donor T cells via the indirect pathway. Donor T-cell activation requires Ag presentation via MHC molecules to the T-cell Ag receptor (TCR), as well as stimulation via various costimulatory molecules. This interaction results in T-cell activation, proliferation, differentiation (Th1, Th2), migration to GVHD target organs, and secretion of various chemokines and cytokines, importantly IFN-γ and IL-2. (C) Cellular and inflammatory effectors lead to target organ tissue damage. CTLs mediate target cell apoptosis via interactions between TNF and TNF receptors, TRAIL (TNF-related apoptosis-inducing ligand)/TRAIL-R and Fas (CD95)/FasL interactions and release of cytotoxic mediators (perforin and granzyme). Recruited macrophages release TNF-α, IL-1, and NO, which also damage target cells. RT indicates radiation therapy; ICAM-1, intercellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1; ICOS, inducible costimulator; and NO, nitric oxide. (A-C) Professional illustrations by Alice Y. Chen.