ALPHA(6) INTEGRINS ARE REQUIRED FOR LANGERHANS CELL-MIGRATION FROM THE EPIDERMIS

Topical exposure of mice to chemical allergens results in the migratio n of epidermal Langerhans cells (LCs) from the skin and their accumula tion as immunostimulatory dendritic cells (DCs) in draining lymph node s. Epidermal cell-derived cytokines have been implicated in the matura tion and migration of LCs, but the adhesion molecules that regulate LC migration have not been studied. We hypothesized that integrin-mediat ed interactions with extracellular matrix components of the skin and l ymph node may regulate LC/DC migration. We found that alpha(6) integri ns and alpha(4) integrins were differentially expressed by epidermal L Cs and lymph node DCs. A majority of LCs (70%) expressed the alpha(6) integrin subunit, whereas DCs did not express alpha(6) integrins. In c ontrast, the alpha(6) integrin subunit was expressed at high levels on DCs but at much lower levels on LCs. The anti-alpha(6) integrin antib ody, GoH3, which blocks binding to laminin, completely prevented the s pontaneous migration of LCs from skin explants in vitro and the rapid migration of LCs from mouse ear skin induced after intradermal adminis tration of TNF-alpha in vivo. GoH3 also reduced the accumulation of DC s in draining lymph nodes by a maximum of 70% after topical administra tion of the chemical allergen oxazolone. LCs remaining in the epidermi s in the presence of GoH3 adopted a rounded morphology, rather than th e interdigitating appearance typical of LCs in naive skin, suggesting that the cells had detached from neighboring keratinocytes and withdra wn cellular processes in preparation for migration, but were unable to leave the epidermis. The anti-alpha(4) integrin antibody PS/2, which blocks binding to fibronectin, had no effect on LC migration from the epidermis either in vitro or in vivo, or on the accumulation of DCs in draining lymph nodes after oxazolone application. RGD-containing pept ides were also without effect on LC migration from skin explants. Thes e results identify an important role for alpha(6) integrins in the mig ration of LC from the epidermis to the draining lymph node by regulati ng access across the epidermal basement membrane. In contrast, alpha(4 ) integrins, or other integrin-dependent interactions with fibronectin that are mediated by the RGD recognition sequence, did not influence LC migration from the epidermis. In addition, alpha(4) integrins did n ot affect the accumulation of LCs as DCs in draining lymph nodes.