Defining the Langerhans cell niche and the anchoring point

郎格汉斯细胞(LC)是一种来源不明的表皮树突状细胞，与毛囊(HF)相关，原因不明。在这项工作中，我们证明了小鼠HFs招募Gr-1高单核细胞衍生LC前体(Pre-LCS)，其表皮进入依赖于CCR2/6，而CCR8抑制LC募集。不同的HF区差异表达CCR2/6配体。峡部表达CCL2，漏斗表达CCL20，膨出中的角质形成细胞产生CCR8配体CCL8。因此，不同的HF角质形成细胞亚群通过产生不同的趋化因子来促进或抑制LC的再增殖，这一特征也在人类中表现出来。LCS/Pre-LCS未能进入小鼠和人类的无毛皮肤，建立了HFs作为LC门户，这是白细胞运输和皮肤炎症调节的新范式(NAT免疫出版中)。为了证明上述发现，我们培育了TACE/Sox9小鼠，并对其进行了表征，这些小鼠发展为进行性脱发，并作为一篇独立的手稿(干细胞，正在出版中)报告了脱发的机制。此外，在这一系列工作中，我们对LCS进行了功能表征。我们发现LC通过表皮紧密连接延伸它们的树突以摄取皮肤表面细菌衍生的毒素来诱导中和抗体，从而保护小鼠免受实验性葡萄球菌烫伤皮肤综合征的影响(Ouchi等人。J Exp Med 2011)。

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).