Hematopoietic stem and progenitor cells were previously found to express Toll-like receptors (TLRs), suggesting that bacterial/viral products may influence blood cell formation. We now show that common lymphoid progenitors (CLPs) from mice with active HSV-1 Infection are biased to dendritic cell (DC) differentiation, and the phenomenon Is largely TLR9 dependent. Similarly, CLPs from mice treated with the TLR9 ligand CpG ODN had little ability to generate CD19+ B lineage cells and had augmented competence to generate DCs. TNFα mediates the depletion of late-stage lymphoid progenitors from bone marrow In many Inflammatory conditions, but redirection of lymphopoiesis occurred In TNFα-1- mice treated with CpG ODN. Increased numbers of DCs with a lymphoid past were Identified in lg gene recombination substrate reporter mice treated with CpG ODN. TLR9 is highly expressed on lymphoid progenitors, and culture studies revealed that those receptors, rather than inflammatory cytokines, accounted for the production of several types of functional DCs. Common myeloid progenitors are normally a good source of DCs, but this potential was reduced by TLR9 ligation. Thus, alternate differentiation pathways mav be used to produce Innate effector cells in health and disease. © 2008 by The American Society of Hematology.