22–24 Conversely, skin-derived DCs were shown to induce E- and P-selectin ligands that are associated with homing to the skin.24,25 The capacity of DCs to instruct T-cell homing properties is related to their ability to produce active metabolites from tissue-derived factors.

Gut-derived DCs produce retinoic acid, which leads to imprinting of the gut-homing phenotype and suppression of the BAY 80-6946 order skin-homing phenotype on T cells.26 Similarly, the active form of vitamin D3, 1,25(OH)(2)D(3), which is produced by skin DCs, induces T-cell expression of the skin-selective chemokine receptor CCR10, while inhibiting the expression of gut-homing receptors α4β7 integrin and CCR9.27 Interestingly, recent data also suggest that the DCs are not the starting point but are instructed by local stromal cells.28,29 Albeit the induction of a specific homing phenotype in primed T cells has been occasionally referred to as ‘imprinting’,23 recent data have rather challenged BAY 73-4506 datasheet the concept of permanent imprinting and

favour the assumption of flexibility in the expression of homing receptors.25 Hypothetically, organ-specific homing could also be explained by continuing selection or re-induction of a given receptor upon recirculation through selected tissues providing antigen-exposure and organ-specific co-signals.30 Efforts to demonstrate the stability of differentially expressed homing receptors in vivo have been made only recently. The expression of ligands for E/P-selectins that serve Fluorouracil mw as homing receptors for inflamed skin has been shown to persist for at least several weeks in vivo

only on a subfraction of T cells. However, upon repeated stimulation under ligand-inducing conditions (presence of IL-12), the stable fraction was increased, and ex vivo isolated selectin-ligand-positive effector/memory cells turned out to be almost completely stable.31 This shows that imprinting of a stable homing phenotype appears possible, but requires repeated stimulation under permissive conditions, similar to findings for the imprinting of a cytokine memory in T cells.32 The above-mentioned studies on the mucosal homing receptor α4β7 in CD8+ T cells suggested that expression of this receptor is not permanent after initial induction.25 In CD4+ T cells, repeated stimulations in the presence of retinoic acid were found to result in a largely persistent expression of α4β7, and, again, ex vivo isolated α4β7-high memory CD4+ cells remained positive for weeks after adoptive transfer (B. Szilagyi and A. Hamann, unpublished). In contrast, stable expression of the chemokine receptor CCR9, which is also induced on CD8+ cells by retinoic acid and considered to contribute to mucosal homing, was not observed (Mora et al.23 and B. Szilagyi and A. Hamann, unpublished).