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*
Institute of Immunology, Vienna International Research Cooperation Center, Novartis Research Institute, Vienna, Austria; and
Institute of Immunology,
Department of Internal Medicine III, Division of Rheumatology, and
§
Department of Dermatology I, University of Vienna, Vienna, Austria
Epithelial Langerhans cells (LC) represent immature dendritic cells
that require TGF-ß1 stimulation for their development. Little is
known about the mechanisms regulating LC generation from their
precursor cells. We demonstrate here that LC development from human
CD34+ hemopoietic progenitor cells in response to TGF-ß1
costimulation (basic cytokine combination GM-CSF plus TNF-
, stem
cell factor, and Flt3 ligand) is associated with pronounced cell
cluster formation of developing LC precursor cells. This
cell-clustering phenomenon requires hemopoietic progenitor cell
differentiation, since it is first seen on day 4 after culture
initiation of CD34+ cells. Cell cluster formation
morphologically indicates progenitor cell development along the LC
pathway, because parallel cultures set up in the absence of exogenous
TGF-ß1 fail to form cell clusters and predominantly give rise to
monocyte, but not LC, development (CD1a-,
lysozyme+, CD14+). TGF-ß1 costimulation of
CD34+ cells induces neoexpression of the homophilic
adhesion molecule E-cadherin in the absence of the E-cadherin
heteroligand CD103. Addition of anti-E-cadherin mAb or mAbs to any
of the constitutively expressed adhesion molecule (CD99, CD31, LFA-1,
or CD18) to TGF-ß1-supplemented progenitor cell cultures inhibits LC
precursor cell cluster formation, and this effect is, with the
exception of anti-E-cadherin mAb, associated with inhibition of LC
generation. Addition of anti-E-cadherin mAb to the culture allows
cell cluster-independent generation of LC from CD34+ cells.
Thus, functional E-cadherin expression and homotypic cell cluster
formation represent a regular response of LC precursor cells to
TGF-ß1 stimulation, and cytoadhesive interactions may modulate LC
differentiation from hemopoietic progenitor
cells.
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