Defining the Langerhans cell niche and the anchoring point

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Langerhans cells(LC) are epidermal dendritic cells with incompletely understood origins that associate with hair follicles(HF) for unknown reasons. In this work, we showed that mouse HFs recruited Gr-1high monocyte-derived LC precursors(pre-LCs), whose epidermal entry was CCR2/6 dependent, whereas CCR8 inhibited LC recruitment. Distinct HF regions differentially expressed CCR2/6 ligands. The isthmus expressed CCL2, the infundibulum expressed CCL20, and keratinocytes in the bulge produced the CCR8 ligand, CCL8. Thus, distinct HF keratinocyte subpopulations promote or inhibit LC repopulation via differential chemokine production, a feature also demonstrated in humans. LCs/Pre-LCs failed to enter hairless skin in both mice and humans, establishing HFs as LC portals, a new paradigm in leukocyte trafficking and regulation of skin inflammation(Nat Immunol, in press). To prove the above findings, we generated and characterized TACE/Sox9 mice, which develop progressive alopecia, and have reported mechanisms of hair loss as an independent manuscript(Stem Cells, in press). Furthermore, during this series of work, we functionally characterized LCs. We showed that LCs extend their dendrites through epidermal tight junctions to uptake skin surface bacteria-derived toxin to induce neutralizing antibodies that protected mice from experimental staphylococcal scalded skin syndrome(Ouchi et al. J Exp Med 2011).