GVHD pathophysiology phase 2: donor T-cell priming and differentiation. Donor CD4 T cells contained within the graft are activated by the inflammatory milieu early after conditioning, facilitating their rapid access to the gut and lymphoid tissue. Once in the gut, MHC class II–expressing recipient nonhematopoietic APCs can initiate priming to host antigens while recipient hematopoietic APC initiate priming in lymphoid tissue. Recipient hematopoietic APCs appear to be the dominant APCs for CD8 T-cell priming. Donor APCs can further contribute to this priming process. Activation in the presence of various cytokines (particularly IL-4, IL-6, and IL-12) instructs T-cell differentiation along specific lineage pathways (type 2, type 17, and type 1, respectively). The transcription factors GATA-3, RORγt, and T-bet are critical for these Th2, Th17, and Th1 differentiation pathways. Tregs are differentiated in the presence of IL-2 and TGFβ (in the absence of IL-6) and abrogate the differentiation of effector T cells via effects on DCs and effector T cells themselves.