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Published online before print July 21, 2005

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(Journal of Leukocyte Biology. 2005;78:921-929.)
© 2005 by Society for Leukocyte Biology

A novel role for Notch ligand Delta-1 as a regulator of human Langerhans cell development from blood monocytes

Natsuki Hoshino^*, Naoyuki Katayama^*,1, Tetsunori Shibasaki^*, Kohshi Ohishi^*, Junji Nishioka, Masahiro Masuya, Yoshihiro Miyahara^*, Masahiko Hayashida, Daiki Shimomura, Takuma Kato^¶, Kaname Nakatani, Kazuhiro Nishii^*, Kagemasa Kuribayashi^¶, Tsutomu Nobori and Hiroshi Shiku^*

^* Departments of Hematology and Oncology,
Laboratory Medicine, and
^¶ Bioregulation, Mie University School of Medicine, Tsu, Japan;
Blood Transfusion Service, Mie University Hospital, Tsu, Japan; and
Tenri Institute of Medical Research, Tenri, Japan

¹Correspondence: Department of Hematology and Oncology, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan. E-mail: n-kata{at}clin.medic.mie-u.ac.jp

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-ß1 (TGF-ß1) are also secreted in the skin. We report here that Delta-1, in concert with GM-CSF and TGF-ß1, 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-1 (MIP-1). In response to CD40 ligand and tumor necrosis factor , 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-1ß 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-ß1, which may be, in part, relevant to the development of human epidermal LCs. Our results extend the functional scope of Notch ligand -1 in human hematopoiesis.

Key Words: granulocyte-macrophage colony-stimulating factor· • transforming growth factor ß1 • CD14

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