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Blood, Vol. 93 No. 4 (February 15), 1999:
pp. 1208-1220
Transforming Growth Factor- 1 Polarizes Murine Hematopoietic
Progenitor Cells to Generate Langerhans Cell-Like Dendritic Cells
Through a Monocyte/Macrophage Differentiation Pathway
Yi Zhang,
Yan-yun Zhang,
Masafumi Ogata,
Pan Chen,
Akihisa Harada,
Shin-ichi Hashimoto, and
Kouji Matsushima
From the Department of Molecular Preventive Medicine and CREST,
School of Medicine, The University of Tokyo, Tokyo, Japan.
We have recently demonstrated that
CD11b /dullCD11c+ and
CD11b+hiCD11c+ dendritic cell (DC)
precursor subsets represent two distinct DC differentiation pathways
from murine bone marrow lineage-phenotype negative
(Lin)c-kit+ hematopoietic progenitor cells
(HPCs) stimulated with granulocyte-macrophage colony-stimulating factor
(GM-CSF) + stem cell factor (SCF) + tumor necrosis factor 
(TNF). We show here that transforming growth factor- 1 (TGF-1)
significantly inhibits the generation of these
CD11b/dullCD11c+ and
CD11b+hiCD11c+ DC precursors.
Phenotypically, this inhibitory effect was accompanied by markedly
suppressed expression of Ia and CD86 antigens as well as major
histocompatibility complex (MHC) class II transactivator (CIITA) and
CC-chemokine receptor 7 (CCR7) mRNAs in
Linc-kit+ HPC cultures stimulated with
GM-CSF + SCF + TNF at day 6. TGF-1 could also suppress mature
DC differentiation from CD11b+hiCD11c+ DC
precursors, but not the differentiation from
CD11b/dullCD11c+ DC precursors. In the
absence of TNF, TGF-1 markedly suppressed the expression of CIITA
and CCR7 mRNAs in GM-CSF + SCF-stimulated Linc-kit+ HPCs at either day 6 or day 12 and induced the differentiation solely into monocytes/macrophages as
evident in morphology, active phagocytic, and endocytic activities.
These cells expressed high levels of F4/80 and E-cadherin antigens, but
low or undetectable levels of Ia, CD86, and CD40 molecules. However,
upon the stimulation with TNF + GM-CSF, these cells could further
differentiate into mature DCs expressing high levels of Ia and
E-cadherin, characteristics for Langerhans cells (LCs), and gained the
capacity of enhancing allogenic MLR. Taken together, all of these
findings suggest that TGF-1 polarizes murine HPCs to generate
LC-like DCs through a monocyte/macrophage differentiation pathway.
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