Introduction:
Human DCs comprise at least four types defined under cytokine-driven conditions in vitro. These include conventional or “myeloid” DCs: (1) CD14+ blood monocyte-derived DCs (moDCs); 2) dermal DCs or interstitial DCs (DDC-IDCs); 3) Langerhans cells (LCs) and 4) plasmacytoid DCs. A trace population of DCs also circulates in human blood. These DCs are lineage negative, CD11c+, CD86+ and HLA-DRbright and express DC83 after activation by brief overnight culture. Although not identical they share many phenotypic and immunostimulatory features with cytokine-generated conventional DCs in vitro.
The most common source for in vitro isolation of human DCs is the peripheral blood, and especially the blood monocytes of myeloid origin, but DCs have also been generated form other tissues, including the bone-marrow, cord blood, thymus, tonsils, skin and synovial fluid.
There are 2 main dendritic cell (DC) subsets that have been identified in humans: the CD11c+myeloid DCs, which include Langherans cells and dermal and interstitial DCs, and the CD11c−/CD123+/CD4+plasmacytoid DCs (pDCs).
Human myeloid and plasmacytoid DC precursors are present in the blood, and precursors of plasmacytoid DCs can also be found in the lymph nodes. Immature myeloid DCs are observed in the epidermis (LCs), the dermis, the interstitial spaces of most tissues and the blood (interstitial DCs). Mature myeloid and plasmocytoid DCs are present in lymphoid tissues, and in low numbers, in the blood.
Human DCs can differentiate from two distinct types of DC precursors in culture: monoctyes and CD4+CD3-CD11c-
Monocyte-derived DC (Blood moDCs):
The most accessible DC precursor is the CD14+ monocyte in peripheral blood, which differentiates into CD14neg, CD11c+, CD83++, HLA-DRbright moDCs under the influence of GM-CSF and IL-4. Blood monocytes give rise either to monocyte-derived DCs when cultured in vitro with GM-CSF and IL-4, or to monocyte derived LC when cultured with GM-CSF and IL-15, or to macrophages in the present of macrophage-CSF (M-CSF) and IL-10. Blood precursor plasmacytoid DCs differentiate into plasmacytoid DCs when cultured with IL-3.
Myeloid DCs (MDCs):
CD11c+ myeloid DCs (MDCs) originate form CD34+ myeloid precursors. Immature MDCs originate in bone marrow and transit to blood, tissues, dermis and mucosa. Under IL-4, GM-CSF conditions, CD14pos monocytes change from phagocytic scavengers with limited antigen presenting capacity to highly potent, CD14ne APCs, termed immature monocyte derived DCs. MDCs in particular, are widely distributed throughout the body and are most prevalent in the skin and mucosal tissues, where they are defined as “immature”.
During viral infection, CD11c+ DCs play an important role in adaptive antiviral immune responses by acquiring and processing viral antigens into peptides for major histocompatibility complex (MHC) presentation to T cells in secondary lymphoid organs. See Bhardwaj
Common myeloid progenitors give rise to two subpopulations, interstitial DC found in peripheral blood and epidermal Langerhans cells (LC). Interstitial DC express CD1, CD11b, CD11c and other myeloid surface molecules including GM-CSF receptor and their growth and survival is dependent on the presence of GM-CSF. When stimulated, interstitial DCs secrete , which is a key cytokine for the induction of Th1 type of immune response. CD11c+CD1a+ Langerhans precursors migrate into the epidermis and become Langerhans cells.
When immature monocyte derived DCs are stimulated by CD40L or proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6, IFN-alpha), they morph into mature monocyte derived DCs which express greater amounts of surface CD80 and CD896 and become CD83 positive which enhances their ability to stimulate T cells. Production of IL-12 is also significantly augmented leading to greater capacity to polarize Th1 cell responses and stimulate cytotoxic T lymphocyte (CTL) effectors. They express lower amounts of DC-SIGN and maintain low CD4 and chemokine receptor expression.
Plasmacytoid DC: (see outline)
Plasmacytoid DC precursors comprise another population identificable in the circulation as linegage negative, HLA-DRbright, BDCA-2+, BDCA-4+, and CD123bright cells. Human plasmacytoid DCs lack myloid markers CD11c and CD33. In contrast, thet express low levels of CD11c along with B220 and Gr1 and express CD123 only after fms-like tyrosine kinase 3 ligand (Flt3-L) treatment.
PDCs differ from other DC types in several respects, including their plasmacytoid morphology, their very immature phenotype, their expression of TLR9 and capacity to be activated by CpG, and their capacity to produce high levels of type I IFN in response to viral stimulation.
Although CD123 is highly expressed by pDC, the surface type II lectin BDCA-2 represents the most specific marker of this population.