Transforming Growth Factor-β1 Polarizes Murine Hematopoietic Progenitor Cells to Generate Langerhans Cell-Like Dendritic Cells Through a Monocyte/Macrophage Differentiation Pathway

Abstract

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-β1 (TGF-β1) 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 Lin−c-kit+ HPC cultures stimulated with GM-CSF + SCF + TNF at day 6. TGF-β1 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-β1 markedly suppressed the expression of CIITA and CCR7 mRNAs in GM-CSF + SCF-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 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-β1 polarizes murine HPCs to generate LC-like DCs through a monocyte/macrophage differentiation pathway.