CD34(+) cell-derived CD14(+) precursor cells develop into Langerhans cellsin a TGF-beta 1-dependent manner

Langerhans cells (LC) are CD1a(+)E-cadherin (E-cad)(+)Birbeck granule(+) bu t CD11b(-)CD36(-)factor XIIIa (FXIIIa)(-) members of the dendritic cell (DC ) family. Evidence holds that LC originate from CD1a(+)CD14(-) rather than CD14(+)CD1a(-) progenitors, both of which arise from GM-CSF/TNF-alpha-stimu lated CD34(+) stem cells. The CD14(+)CD1a(-) progenitors, on the other hand , can give rise to a separate DC type characterized by its CD1a(+)CD11b(+)C D36(+)FXIIIa(+)E-cad(-)BG(-) phenotype (non-LC DC). Although GM-CSF/TNF-alp ha are important for both LC and non-LC DC differentiation, TGF-beta 1 is t hought to preferentially promote LC development in, vitro and in vivo. Howe ver, the hemopoietic biology of this process and the nature of TGF-beta 1-r esponsive LC precursors (LCp) are not well understood. Here we show that CD 14(+) precursors in the presence, but not in the absence,of TGF-beta 1 give rise to a progeny that fulfills all major criteria of LC. In contrast, LC development from CD1a(+) progenitors was TGF-beta 1 independent. Further st udies revealed that CD14(+) precursors contain a CD11b(+) and a CD11b(-) su bpopulation. When either subset was stimulated with GM-CSF/TNF-alpha and TG F-beta 1, only CD14(+)CD11b(-) cells differentiated into LC. The CD11b(+) c ells, on the other hand, acquired non-LC DC features only. The higher doubl ing rates of cells entering the CD14(+) LCp rather than the CD1a(+) LCp pat hway add to the importance of TGF-beta 1 for LC development. Because CD14()CD11b(-) precursors are multipotent cells that can enter LC or macrophage differentiation, it is suggested that these cells, if present at the tissue level, endow a given organ with the property to generate diverse cell type s in response to the local cytokine milieu.