Published online before print September 6, 2007

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(American Journal of Pathology. 2007;171:1249-1257.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070225

CXCL12-CXCR4 Engagement Is Required for Migration of Cutaneous Dendritic Cells

Kenji Kabashima^*, Noriko Shiraishi^*, Kazunari Sugita^*, Tomoko Mori^*, Ayako Onoue^*, Miwa Kobayashi^*, Jun-ichi Sakabe^*, Ryutaro Yoshiki^*, Hirokazu Tamamura, Nobutaka Fujii, Kayo Inaba and Yoshiki Tokura^*

From the Department of Dermatology,^* University of Environmental and Occupational Health, Yahatanishi-ku, Kitakyushu; the Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo; the Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto; and the Department of Animal Development and Physiology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan

CCR7 is regarded as an essential chemokine receptor for cutaneous dendritic cell (DC) migration into the regional lymph nodes. However, complete migratory inhibition cannot be obtained in CCR7-deficient mice, suggesting that there exist other chemokine receptors involved in this process. Initially, we found that CXCR4 was highly expressed on migrated cutaneous DCs and that its ligand, CXCL12, was detected in the LYVE-1⁺ lymphatic vessels in the skin. FITC-induced cutaneous DC migration into the draining lymph nodes was impaired by the specific CXCR4 antagonist 4-F-Benzoyl-TN14003. Among FITC⁺ cells, Langerin⁺ Langerhans cells and Langerin^– (dermal) dDC subsets were detected as CD11c^high+CD11b^int+ cells and CD11c^high+CD11b^high+ plus CD11c^low+CD11b^int+ cells, respectively, both of which were suppressed by CXCR4 antagonist. Moreover, in vivo contact hypersensitivity response was impaired by CXCR4 antagonist administered during the sensitization phase. The in vitro proliferative response to dinitrobenzene sulfonic acid of sensitized lymph node cells was inhibited by CXCR4 antagonist treatment. These findings demonstrated that CXCL12-CXCR4 engagement on cutaneous DCs plays a crucial role in the initiation of skin immune response by enhancing cutaneous DC migration.

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