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Epidermal and Dermal Dendritic Cells Display Differential Activation and Migratory Behavior While Sharing the Ability to Stimulate CD4⁺ T Cell Proliferation In Vivo^1,2

Centenary Institute of Cancer Medicine and Cell Biology, Faculty of Medicine, University of Sydney, New South Wales, Australia

Migrated Langerhans cells (m-LCs) have recently been shown to comprise only a minority of skin-derived dendritic cells (DCs) expressing Langerin in cutaneous lymph nodes. We have used BM chimeric mice that differ in CD45 and MHC class II alleles to unequivocally distinguish between radioresistant m-LCs and radiosensitive migrated dermal DCs (m-dDCs), to determine their phenotype, response to contact sensitization, and ability to activate naive CD4⁺ T cells in vivo. We have also characterized three subsets of dDCs and their migratory counterparts, as distinguished by expression of CD11b and Langerin. Each of the four subsets of skin DCs showed differential migration to draining LN in response to contact sensitizing agents. Migration of Langerin^–CD11b⁺ and Langerin⁺CD11b^low dDCs peaked after 1 day, followed by Langerin^–CD11b^low dDCs at 2 days and Langerin⁺ LCs at 4 days. Moreover, while m-LCs and m-dDCs had similar surface phenotypes in the steady state, they displayed unexpectedly different activation responses to contact sensitization: m-dDCs markedly up-regulated CD80 and CD86 at day 1, whereas only m-LCs up-regulated CD40, with delayed kinetics. Thus, m-dDCs are likely to be responsible for the initial response to skin immunization. However, when expression of cognate MHC class II was restricted to LCs and m-LCs, they were also capable of processing and presenting protein Ag to drive naive CD4 T cell proliferation in vivo. Thus, m-dDCs and m-LCs display distinct behavior in cutaneous lymph nodes while sharing the ability to interact specifically with T cells to control the immune response.

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¹ This work was supported by a Program Grant from the Australian National Health and Medical Research Council. B.F.d.S.G. is a National Health and Medical Research Council Principal Research Fellow.

² E.S. designed and performed research and wrote paper, B.R. designed and performed research and contributed to writing paper, and B.F.d.S.G. designed research and wrote paper.

³ Address correspondence and reprint requests to Dr. Barbara Fazekas de St. Groth, Centenary Institute of Cancer Medicine and Cell Biology, Locked Bag No. 6, Newtown, New South Wales 2042, Australia. E-mail address: b.fazekas{at}centenary.usyd.edu.au

⁴ Abbreviations used in this paper: DC, dendritic cell; m-DC, migratory DC; dDC, dermal DC; LC, Langerhans cell; cLN, cutaneous lymph node; BM, bone marrow; MCC, moth cytochrome c; HELMCC, hen egg lysozyme-MCC fusion protein; HEV, high endothelial venule; int, intermediate; CI, Centenary Institute; DAPI, 4',6-diamidino-2-phenylindole; FSC, forward scatter; 5FU, 5-fluorouracil.