A novel role for Notch ligand Delta-1 as a regulator of human Langerhans cell development from blood monocytes.
Human Langerhans cells (LCs) are of hematopoietic origin, but cytokine regulation of their development is not fully understood. Notch ligand Delta-1 is expressed in a proportion of the skin. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor-beta1 (TGF-beta1) are also secreted in the skin. We report here that Delta-1, in concert with GM-CSF and TGF-beta1, induces the differentiation of human CD14(+) blood monocytes into cells that express LC markers: CD1a, Langerin, cutaneous lymphocyte-associated antigen, CC chemokine receptor 6, E-cadherin, and Birbeck granules. The resulting cells display phagocytic activity and chemotaxis to macrophage inflammatory protein-1alpha (MIP-1alpha). In response to CD40 ligand and tumor necrosis factor alpha, the cells acquire a mature phenotype of dendritic cells that is characterized by up-regulation of human leukocyte antigen (HLA)-ABC, HLA-DR, CD80, CD86, CD40, and CD54 and appearance of CD83. These cells in turn show chemotaxis toward MIP-1beta and elicit activation of CD8(+) T cells and T helper cell type 1 polarization of CD4(+) T cells. Thus, blood monocytes can give rise to LCs upon exposure to the skin cytokine environment consisting of Delta-1, GM-CSF, and TGF-beta1, which may be, in part, relevant to the development of human epidermal LCs. Our results extend the functional scope of Notch ligand delta-1 in human hematopoiesis.
Hoshino
Natsuki
N
Department of Hematology and Oncology, Mie University School of Medicine, Mie 514-8507, Japan. n-kata@clin.medic.mie-u.ac.jp
Katayama
Naoyuki
N
Shibasaki
Tetsunori
T
Ohishi
Kohshi
K
Nishioka
Junji
J
Masuya
Masahiro
M
Miyahara
Yoshihiro
Y
Hayashida
Masahiko
M
Shimomura
Daiki
D
Kato
Takuma
T
Nakatani
Kaname
K
Nishii
Kazuhiro
K
Kuribayashi
Kagemasa
K
Nobori
Tsutomu
T
Shiku
Hiroshi
H
D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D051792:Basic Helix-Loop-Helix Proteins / Q000187:drug effects / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D016764:Cell Polarity / Q000502:physiology; D002478:Cells, Cultured; D002633:Chemotaxis / Q000502:physiology; D010450:Endopeptidases / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000187:drug effects / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007801:Langerhans Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D008024:Ligands; D018950:Lipopolysaccharide Receptors / Q000097:blood* / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000494:pharmacology / Q000502:physiology*; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D010641:Phenotype; D000072056:Transcription Factor HES-1; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D051792:Basic Helix-Loop-Helix Proteins; D010450:Endopeptidases; D004791:Enzyme Inhibitors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D018950:Lipopolysaccharide Receptors; D008565:Membrane Proteins; D000072056:Transcription Factor HES-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C508960:TGFB1 protein, human; C064045:delta protein; C078493:HES1 protein, human; C509280:BACE1 protein, human