Hematopoietic development of human dendritic cells.

All human DCs develop originally from CD34+ hematopoietic progenitor cells (HPCs) from either bone marrow, cord blood, or cytokine-elicited peripheral blood stem cells. Expansion is supported in vitro by factors like FLT-3-ligand (FL; c-fms-like tyrosine kinase ligand) and c-kit-ligand or stem cell factor (KL/SCF), with additional contributions from either granulocyte-macrophage colony stimulating factor (GM-CSF) or interleukin 3 (IL-3). GM-CSF supports myeloid DC expansion and differentiation, whereas IL-3 supports that of lymphoid-related DCs (also called plasmacytoid DCs, or IPCs, for natural interferon producing cells). Tumor necrosis factor-alpha (TNF) exerts pleiotropic effects, recruiting transferrin receptor positive CD34+ HPCs into cell cycle, at least partially suppressing G-CSF and M-CSF receptors early in CD34+ HPC differentiation, and later supporting terminal DC maturation. Additional cytokines like interleukin 4 (IL-4) and transforming growth factor-beta 1 (TGF) suppress CD14+ macrophage differentiation, and IL-4 is especially useful in this respect. TGF supports the differentiation of Langerhans cells (LCs), instead of dermal/interstitial DCs (DDC/IDCs). DDC/IDCs and monocyte-derived DCs (moDCs) are considered comparable progeny, with development of the former defined from CD34+ HPCs via a CD14+ bipotential intermediate and development of the latter defined from peripheral blood monocytes. Pertinent to approaches that require dividing cells for introducing antigen, like some forms of gene transfer, it should be noted that DC precursors as represented here are no longer in cell cycle. Note also that immature DCs require some form of terminal maturation and activation stimulus in order not to revert to an immature state or to an alternative differentiation pathway, usually supplied in vivo by bacterial products like lipopolysaccharide (LPS) or reactive T lymphocyte, but mimicked in vitro by certain cytokines as shown (including interleukin 1, IL-1; interleukin-6, IL-6; prostaglandin E2, PGE2; interferon-alpha and beta, IFN; CD40-ligand, CD40L). CD83 remains the best available marker of terminally matured DCs, and it is never expressed by committed macrophages. Additional maturation/activation epitopes are discussed in the text. Note that not all mature/activated LCs continue to express Langerin, but none of the DDC/IDCs or moDCs express this antigen. CD1a does not discriminate between LCs and DDC/IDC/moDCs, as it is expressed by all myeloid DC types.