BACKGROUND & AIMS:: Lymphocytes primed by intestinal dendritic cells (DC) express the gut-homing receptors CCR9 and a4ss7 which recognise CCL25 and MAdCAM-1 in the intestine promoting the development of regional immunity. In mice imprinting of CCR9 and a4ss7 is dependent on retinoic acid (RA) during T cell activation. Tissue-specificity is lost in primary sclerosing cholangitis (PSC), an extraintestinal manifestation of inflammatory bowel disease, when ectopic expression of MAdCAM-1 and CCL25 in the liver promotes recruitment of CCR9+a4ss7+ T cells to the liver. We investigated the processes that control entero-hepatic T cell migration and whether the ability to imprint CCR9 and a4ss7 is restricted to intestinal DCs or can under some circumstances be acquired by hepatic DCs in diseases such as PSC. METHODS:: Human and murine DCs from gut, liver or portal lymph nodes and hepatic stellate cells were used to activate CD8 T-cells. Imprinting of CCR9 and a4ss7 and functional migration responses were determined. Cross-over activation protocols assessed plasticity of gut-homing. RESULTS:: Activation by gut DCs imprinted high levels of functional CCR9 and a4ss7 on naïve CD8 T cells whereas hepatic DCs and stellate cells proved inferior. Imprinting was RA-dependent and demonstrated plasticity. CONCLUSIONS:: Imprinting and plasticity of gut-homing human CD8 T-cells requires primary activation or reactivation by gut DCs and is RA-dependent. The inability of liver DCs to imprint gut-tropism implies that a4ss7+CCR9+ T cell that infiltrate the liver in PSC are primed in the gut.