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Published online before print July 21, 2005

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1204746

Received for publication December 22, 2004.
Revised May 31, 2005.
Accepted for publication June 29, 2005.

Article

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

Natsuki Hoshino ^*, Naoyuki Katayama ^*@, 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, Nara, Japan

^@ To whom correspondence should be addressed. E-mail: n-kata{at}clin.medic.mie-u.ac.jp.

	Abstract

Human Langerhans cells (LCs) are of hematopoietic origin, but cytokine regulation of their development is not fully understood. Notch ligand -1 is expressed in a proportion of the skin. Granulocyte macrophage-colony stimulating factor (GM-CSF) and transforming growth factor-1 (TGF-1) are also secreted in the skin. We report here that -1, in concert with GM-CSF and TGF-1, 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-1 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 -1, GM-CSF, and TGF-1, 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 1 • CD14

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