The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/11/1725/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 10, November 17, 1997 1725-1735

Articles

{alpha}6 Integrins Are Required for Langerhans Cell Migration from the Epidermis

Abigail A. Price*, Marie Cumberbatch{ddagger}, Ian Kimber{ddagger}, and Ann Ager*

From the * Division of Cellular Immunology, National Institute for Medical Research, Mill Hill, London, NW7 1AA, United Kingdom; and {ddagger} Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, SK10 4TJ, United Kingdom

Topical exposure of mice to chemical allergens results in the migration of epidermal Langerhans cells (LCs) from the skin and their accumulation as immunostimulatory dendritic cells (DCs) in draining lymph nodes. Epidermal cell–derived cytokines have been implicated in the maturation and migration of LCs, but the adhesion molecules that regulate LC migration have not been studied. We hypothesized that integrin-mediated interactions with extracellular matrix components of the skin and lymph node may regulate LC/DC migration. We found that {alpha}6 integrins and {alpha}4 integrins were differentially expressed by epidermal LCs and lymph node DCs. A majority of LCs (70%) expressed the {alpha}6 integrin subunit, whereas DCs did not express {alpha}6 integrins. In contrast, the {alpha}4 integrin subunit was expressed at high levels on DCs but at much lower levels on LCs. The anti-{alpha}6 integrin antibody, GoH3, which blocks binding to laminin, completely prevented the spontaneous migration of LCs from skin explants in vitro and the rapid migration of LCs from mouse ear skin induced after intradermal administration of TNF-{alpha} in vivo. GoH3 also reduced the accumulation of DCs in draining lymph nodes by a maximum of 70% after topical administration of the chemical allergen oxazolone. LCs remaining in the epidermis in the presence of GoH3 adopted a rounded morphology, rather than the interdigitating appearance typical of LCs in naive skin, suggesting that the cells had detached from neighboring keratinocytes and withdrawn cellular processes in preparation for migration, but were unable to leave the epidermis.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 peptides were also without effect on LC migration from skin explants.

These results identify an important role for {alpha}6 integrins in the migration of LC from the epidermis to the draining lymph node by regulating 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 not affect the accumulation of LCs as DCs in draining lymph nodes.

Address correspondence to Ann Ager, Division of Cellular Immunology, National Institute for Medical Research, Mill Hill, London, NW7 1AA, UK. Phone: 44-181-959-3666, ext 2465; FAX: 44-181-913-8529; E-mail: a-ager{at}nimr.mrc.ac.uk

We would like to acknowledge the excellent technical assistance of Chris Atkins for flow cytometry, John Asante for histology, and Joe Brock for the figures.

This work was funded by the Medical Research Council (MRC, UK). Abigail Price was the recipient of an MRC Collaborative Studentship in conjunction with Zeneca.

1 Abbreviations used in this paper: BM, basement membrane; DC, dendritic cell; ECM, extracellular matrix; GRDGS, Gly-Arg-Asp-Gly-Ser; GRGDS, Gly-Arg-Gly-Asp-Ser; HRP, horseradish peroxidase; LC, Langerhans cell; RGD, Arg-Gly-Asp; SA, streptavidin; VCAM, vascular cell adhesion molecule.


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