Abstract
Langerhans cells (LCs) are epidermal dendritic cells with incompletely understood origins that associate with hair follicles for unknown reasons. Here we show that in response to external stress, mouse hair follicles recruited Gr-1hi monocyte-derived precursors of LCs whose epidermal entry was dependent on the chemokine receptors CCR2 and CCR6, whereas the chemokine receptor CCR8 inhibited the recruitment of LCs. Distinct hair-follicle regions had differences in their expression of ligands for CCR2 and CCR6. The isthmus expressed the chemokine CCL2; the infundibulum expressed the chemokine CCL20; and keratinocytes in the bulge produced the chemokine CCL8, which is the ligand for CCR8. Thus, distinct hair-follicle keratinocyte subpopulations promoted or inhibited repopulation with LCs via differences in chemokine production, a feature also noted in humans. Pre-LCs failed to enter hairless skin in mice or humans, which establishes hair follicles as portals for LCs.
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Acknowledgements
We thank K. Eguchi and H. Ito for assistance, and M. Kajimura for assistance with multiphoton microscopy. Supported by the Japan Society for the Promotion of Science (K.N. and M.A.), The Kanae Foundation for the Promotion of Medical Science, and Japaneses Dermatological Association (K.N.), The Netherlands Organization for Scientific Research (B.E.C.) and the Intramural Research Program of the Center for Cancer Research of the National Cancer Institute (M.C.U.).
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K.N. conceived of and designed all experiments; K.N. and T.K. did experiments, with the assistance of K.Mo., T.A., D.Y.M., S.U., K.H., M.O., A.K. and Y.C.; B.E.C. provided Langerin-DTR mice; K.Ma. provided bone marrow from mice deficient in CCR1, CCR2 or CCR5 and Cx3cr1gfp/gfp mice; G.C.F. and S.A.L. provided bone marrow from CCR8-deficient mice; J.M.F. provided bone marrow from CCR6-deficient mice; H.T., K.K. and M.S. assisted with multiphoton intravital microscopy; K.Mo. assisted with the sorting of hair-follicle keratinocytes; M.C.U. and M.A. interpreted data and guided the project; and K.N. and M.C.U. wrote the manuscript.
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Supplementary Text and Figures
Supplementary Figures 1–4 and Table 1 (PDF 556 kb)
Supplementary Video 1
Multi-photon microscopy of DC recruitment to skin in vivo. (MOV 12159 kb)
Supplementary Video 2
Multi-photon microscopy of pre-LCs repopulation via HFs. (MOV 52721 kb)
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Nagao, K., Kobayashi, T., Moro, K. et al. Stress-induced production of chemokines by hair follicles regulates the trafficking of dendritic cells in skin. Nat Immunol 13, 744–752 (2012). https://doi.org/10.1038/ni.2353
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DOI: https://doi.org/10.1038/ni.2353
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