Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 210, Issue 12, Pages 2597-2610Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20130275
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Funding
- High Education Commission of Pakistan
- Austrian Science Fund (FWF) grants [P22058, P19245, P25720, SFB-2304, P23215-B11]
- PhD program W1212 Inflammation and Immunity
- FWF grant [P19474-B13]
- Austrian Science Fund (FWF) [P19245, P19474, P22058, P23215, P25720, W1212] Funding Source: Austrian Science Fund (FWF)
- Austrian Science Fund (FWF) [P 23215, P 25720] Funding Source: researchfish
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Human Langerhans cell (LC) precursors populate the epidermis early during prenatal development and thereafter undergo massive proliferation. The prototypic antiproliferative cytokine TGF-beta 1 is required for LC differentiation from human CD34(+) hematopoietic progenitor cells and blood monocytes in vitro. Similarly, TGF-beta 1 deficiency results in LC loss in vivo. However, immunohistology studies revealed that human LC niches in early prenatal epidermis and adult basal (germinal) keratinocyte layers lack detectable TGF-beta 1. Here we demonstrated that these LC niches express high levels of bone morphogenetic protein 7 (BMP7) and that Bmp7-deficient mice exhibit substantially diminished LC numbers, with the remaining cells appearing less dendritic. BMP7 induces LC differentiation and proliferation by activating the BMP type-I receptor ALK3 in the absence of canonical TGF-beta 1-ALK5 signaling. Conversely, TGF-beta 1-induced in vitro LC differentiation is mediated via ALK3; however, co-induction of ALK5 diminished TGF-beta 1-driven LC generation. Therefore, selective ALK3 signaling by BMP7 promotes high LC yields. Within epidermis, BMP7 shows an inverse expression pattern relative to TGF-beta 1, the latter induced in suprabasal layers and up-regulated in outer layers. We observed that TGF-beta 1 inhibits microbial activation of BMP7-generated LCs. Therefore, TGF-beta 1 in suprabasal/outer epidermal layers might inhibit LC activation, resulting in LC network maintenance.
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