Plasmacytoid Dendritic Cell

Plasmacytoid dendritic cells (pDCs) are a rare type of immune cell that are known to secrete large quantities of type 1 interferon (IFNs) in response to a viral infection. They circulate in the blood and are found in peripheral lymphoid organs. They develop from bone marrow hematopoietic stem cells and constitute < 0.4% of peripheral blood mononuclear cells (PBMC). Other than conducting antiviral mechanisms, pDCs are considered to be key in linking the innate and adaptive immune systems. However, pDCs are also responsible for participating in and exacerbating certain autoimmune diseases like lupus. pDCs that undergo malignant transformation cause a rare hematologic disorder, blastic plasmacytoid dendritic cell neoplasm.

Development and characteristics

In the bone marrow, common dendritic cell progenitors expressing Flt3 (CD135) receptors are able to give rise to pDCs. Flt3 or CD135 signaling induces differentiation and proliferation of pDCs, although their mechanisms are not entirely understood. Phosphoinositide 3-kinase (PI3K)-dependent activation of mechanistic target of rapamycin (mTOR) is believed to regulate this signaling pathway. Transcription factor E2-2 has also been found to play a key role in influencing the lineage commitment of a common DC progenitor on its course to becoming a pDC.

Unlike conventional dendritic cells (cDCs) that leave the bone marrow as precursors, pDCs leave the bone marrow to go to the lymphoid organs and peripheral blood upon completing development. Plasmacytoid dendritic cells are also distinguished from cDCs because of their ability to produce significant amounts of type-1 interferon. pDC maturation is initiated when the cell comes in contact with a virus, prompting the upregulation of MHC class I and MHC class II, co-stimulatory molecules CD80, CD86, CD83, and c-c chemokine receptor 7 (CCR7) and interferon production gradually decreases. CCR7 expression prompts the matured pDC to migrate to a lymph node where it will be able to stimulate and interact with T cells.

In humans, pDCs exhibit plasma cell morphology and express CD4, HLA-DR, CD123, blood-derived dendritic cell antigen-2 ( BDCA-2), Toll-like receptor (TLR) 7 and TLR9 within endosomal compartments. Expression of TLR 7 and TLR 9 allows pDCs to interact with viral and host nucleic acids. TLR 7 and TLR 9 detect ssRNA and unmethylated CpG DNA sequences, respectively. ILT7 and BDCA-4 are also expressed on human pDC surfaces, although their signaling pathways are still obscure. However, there are speculations that the interaction between ILT7 and BST2 may have a negative regulatory effect on the cell’s interferon production. Unlike myeloid dendritic cells, myeloid antigens like CD11b, CD11c, CD13, CD14 and CD33 are not present on pDC surfaces. Furthermore, pDCs express markers CD123, CD303 (BDCA-2) and CD304 unlike other dendritic cell types.

Blastic plasmacytoid dendritic cell neoplasm

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare type of myeloid cancer in which malignant pDCs infiltrate the skin, bone marrow, central nervous system, and other tissues. Typically, the disease presents with skin lesions (e.g. nodules, tumors, papules, bruise-like patches, and/or ulcers) that most often occur on the head, face, and upper torso. This presentation may be accompanied by cPC infiltrations into other tissues to result in swollen lymph nodes, enlarged liver, enlarged spleen, symptoms of central nervous system dysfunction, and similar abnormalities in breasts, eyes, kidneys, lungs, gastrointestinal tract, bone, sinuses, ears, and/or testes. The disease may also present as a pDC leukemia, i.e. increased levels of malignant pDC in blood (i.e. >2% of nucleated cells) and bone marrow and evidence (i.e. cytopenias) of bone marrow failure. Blastic plasmacytoid dendritic cell neoplasm has a high rate of recurrence following initial treatments with various chemotherapy regimens. In consequence, the disease has a poor overall prognosis and newer chemotherapeutic and novel non-chemotherapeutic drug regimens to improve the situation are under study.

Role in immunity

Upon stimulation and subsequent activation of TLR7 and TLR9, these cells produce large amounts (up to 1,000 times more than other cell type) of type I interferon (mainly IFN-α and IFN-β), which are critical anti-viral compounds mediating a wide range of effects and induce maturation of the pDC. For example, the secretion of type 1 interferon triggers natural killer cells to produce IFNγ while also activating the differentiation of B cells. In addition, they can produce cytokines IL-12, IL-6 and TNF-α as well, helping to recruit other immune cells to the site of infection.

Because they are capable of activating other immune cells, pDCs serve as a bridge between innate