Transforming growth factor-β1 polarizes murine hematopoietic progenitor cells to generate Langerhans cell-like dendritic cells through a monocyte/macrophage differentiation pathway

We have recently demonstrated that CD11b(-/dull)CD11c(+) and CD11b(+hi)CD11c(+) 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 alpha (TNF alpha). We show here that transforming growth factor-beta 1 (TGF-beta 1) significantly inhibits the generation of these CD11b(-/dull)CD11c(+) and CD11b(+hi)CD11c(+) DC precursors. Phenotypically, this inhibitory effect was accompanied by markedly suppressed expression of la and CD86 antigens as well as major histocompatibility complex (MHC) class II transactivator (CIITA) and CC-chemokine receptor 7 (CCR7) mRNAs in Lin(-)c-kit(+) HPC cultures stimulated with GM-CSF + SCF + TNF alpha at day 6. TGF-beta 1 could also suppress mature DC differentiation from CD11b(+hi)CD11c(+) DC precursors, but not the differentiation from CD11b(-/dull)CD11c(+) DC precursors. In the absence of TNF alpha, TGF-beta 1 markedly suppressed the expression of CIITA and CCR7 mRNAs in GM-CSF + SGF-stimulated Lin(-)c-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 la, CD86, and CD40 molecules. However, upon the stimulation with TNF alpha + GM-CSF, these cells could further differentiate into mature DCs expressing high levels of la 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-beta 1 polarizes murine HPCs to generate LC-like DCs through a monocyte/macrophage differentiation pathway. (C) 1999 by The American Society of Hematology.