Plasmacytoid dendritic cells and type I IFN: 50 years of convergent history

Abstract

It has been 50 years since the initial descriptions of what are now known as plasmacytoid dendritic cells (pDC) and type I IFN. pDC, which are infrequent cells found in the peripheral blood and lymphoid organs, are the most potent producers of type I and type III IFNs in the body. pDC produce IFN-alpha in response to both DNA and RNA enveloped viruses by virtue of their ribonucleic acids signaling in the endosome through TLR9 and TLR7, respectively. This stimulation, which also occurs with DNA or RNA-containing immune complexes and synthetic TLR7 and -9 agonists, is dependent upon the transcription factor IRF-7, which is expressed at high constitutive levels in pDC. In addition to releasing as much as 3-10pg of IFN-alpha/cell, pDC are also potent modulators of the immune response. In this review, we discuss the signaling pathways in pDC, their roles in linking innate and adaptive immunity, and their roles in infectious disease and autoimmunity.

Figure 1. Signaling pathways in pDC leading to induction of IFNs and inflammatory cytokines

pDC have been demonstrated to respond to viral RNA and DNA through a unique molecular complex known as the “cytoplasmic transductional-transcriptional processor” (CTTP) (86). Virus enters the cell either by endocytosis or, potentially, direct fusion with the cell membrane. It is uncoated in the acidic endosome and the viral DNA or RNA interacts with TLR9 or TLR7, respectively. Intracellular signaling occurs through the CTTP, which can contain either IRF-5 or IRF-7. IRAK4 phosphorylates IRAK-1, which in turn is responsible for IRF-7 phosphorylation. IRF-7 is required for the transcription of IFNA genes, while IRF-5 is involved in transcription of inflammatory cytokines. Recent evidence, however, suggests that IRF-5 is also required for IFN-α production. IRF-8 is also expressed in pDC, but its function in IFN induction is not known. Viruses that enter the cytoplasm and replicate may induce IFN-α through TLR7/9-independent pathways (shown with question marks); alternatively, viral RNA or DNA may enter the endosome through autophagy (not shown in figure), thus entering the TLR7/9 pathway.

Figure 2. pDC at the interface of innate and adaptive immunity

pDC respond to stimulation with viruses, CpG and DNA or RNA-containing immune complexes with the production of IFN-α, IFN-λ and pro-inflammatory cytokines. pDC then, either directly in a cell-contact dependent manner or via their soluble products, activate components of the innate (NK, monocytes, myeloid (conventional) DC) responses. Activated pDC migrate to the lymph node, upregulate co-stimulatory molecules and present (or cross-present) antigen to CD4, CD8 cells or Treg. Depending on the nature of the stimulus, pDC may activate Th1 responses (typically in response to viruses) or Th2 (in non-IFN-α stimulating conditions). pDC have also been implicated in the development of B cell maturation to antibody-secreting plasma cells and in establishment of immunological memory.

Figure 3. PDC-derived interferon and the immune response

Induction of IFN production by pDC results in an altered immune response. A deviation to either extreme will result in a pathological condition. pDC deficiency leading to low levels of IFN-α production will result in an inadequate immune response allowing for susceptibility to viral infections, whereas overly high levels of IFN-α can induce hyper immune activation, which may lead to autoimmune conditions or, in the case of HIV-infection, CD4 death.