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

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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-α 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 3–10 pg of IFN-α/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.

Introduction

Scientific progress is often marked by independent investigations leading to the same discovery, and sometimes by independent discoveries that would appear initially to be unrelated, but in the end, are recognized as being inextricably intertwined. The latter situation describes the convergence of the half-century history of the field of interferon research with the fifty years since pathologists first described the cells we now know as plasmacytoid dendritic cells (pDC).

In 1957, Isaacs and Lindenmann published their first paper on interferon [1]; the two scientists were investigating a well-known phenomenon known as “viral interference”, wherein one virus is able to block the infection by a second virus when both are used in the same culture. In the course of their studies they determined that, rather than being mediated by a component of the first virus, as they had hypothesized, the interference instead was mediated by a soluble factor that could be transferred to an uninfected culture and confer virus-resistance on that culture. This discovery of the substance they termed “the interferon” provided the impetus for the development of the whole field of interferon biology that continues to be vigorous to this day. Interferon, like most of the early cytokines that followed it, was named for its first observed biological function: prevention of viral infection. It was not for a couple of decades, however, that the role of interferon beyond “interference” began to be appreciated. Thus, although the designation “interferon” has stuck (unlike the early designations for some of cytokines, such as “T cell growth factor (TCGF)”, which were replaced by less-descriptive interleukin designations), the interferons are now well-appreciated for their roles not just as anti-viral agents, but also as immune modulators and cell growth regulators.

In the course of studies of virus interactions with mononuclear cells in the peripheral blood, it was found that type I interferons (IFNs) were rapidly produced and released into the culture supernatants [2], [3]. Although the primary type I IFN producing cell in the peripheral blood was initially assumed to be a monocyte [4], it was subsequently determined by several research groups, including ours, that the cell in blood that produced the majority of the IFN in response to enveloped viruses was a low frequency, MHC Class II positive cell distinct from T cells, B cells, monocytes and NK cells [5], [6], [7], [8]. Although many cell types in the body are capable of producing type I IFN, these lineage-negative cells were found to be particularly potent, with a single cell able to produce 1–2 IU of IFN in response to viral stimulus, an amount that is 10–100 times more than most other cells. These cells were termed “natural IFN producing cells” or “NIPC” by Gunnar Alm's group in Uppsala, Sweden, with the “natural” referring to their belonging to the early, innate immune response, then known as “natural immunity” [6]. Through the persistent efforts of a small number of groups in both Europe and the United States, including our own, who studied the NIPC, much was learned about the function of these potent IFN-producing cells. Morphologically, the NIPC are large cells with an abundant cytoplasm and an apparent well-developed rough endoplasmic reticulum. Evidence from our group and the Rinaldo group pointed towards the cells being related to the family of dendritic cells [9], [10], [11]; however, it was clear that they were distinct from classical DC, which did not produce IFN-α [12].

In 1958, shortly after the seminal paper by Isaacs and Lindenmann, pathologists Lennert and Remmele described the presence of cells with a plasma cell-like morphology located in what are now known to be the T cell zones of human lymph nodes and spleen [13]). These cells were subsequently found to be prevalent in the lymphoid tissues in pathological conditions including Hodgkin's lymphoma, Castleman's disease and Hodgkin's disease (reviewed in [14]). Major progress into the nature and function of these cells, however, had to await the development of the modern field of cellular immunology and the sub-speciality field of dendritic cell biology. Several decades after their initial description by Lennert and Remmele, these cells were erroneously identified as either “plasmacytoid T cells” [15], [16] or “plasmacytoid monocytes” [17] based on their cell surface markers and lymphoid tissue localization. The identity of the cells as dendritic cells came from Liu and coworkers who isolated them from the T cell-rich areas near the high endothelial venules in tonsils [16]; they termed these cells “DC2” based on their maturation into Th2-inducing DC upon culture with IL-3 and CD40 ligand. The DC2, as shown by electron microscopy had abundant cytoplasm with extensive endoplasmic reticulum (hence their apparent similarity to plasma cells, from which the name “plasmacytoid” derives), indicating that they were poised to produce a large amount of protein; however, what that protein was remained to be determined.

It was after this point that the then 40+-year histories of interferon and the pDC converged: in 1999 it was determined that the NIPC, which made large quantities of interferon-α (IFN-α) in response to a variety of viral and synthetic stimuli, were identical to the plasmacytoid subset of dendritic cells [18], a finding that was soon confirmed [17]. Some of the key cell-surface markers present on human pDC are shown in Table 1. Since that initial identification of the IFN producing cells as pDC, there has been a virtual explosion of research in the area of pDC/IFN biology, with many scientists worldwide joining what was once a very small number of groups investigating NIPC. Because there have been recent reviews, including one of our own [19], detailing the history behind the discovery of pDC and their identity with NIPC, the remainder of this review will focus on the current knowledge about the function and regulation of IFN-α production by pDC and the role of these cells in viral infection, autoimmunity, and other human disease.

Section snippets

Origin of pDC and their relationship to conventional dendritic cells (cDC)

In the field of dendritic cell biology, by far the most work has been carried out using what are now commonly termed “conventional” or cDC. These cells, also known as myeloid dendritic cells (or mDC) are known to differentiate from the common myeloid hematopoietic precursor. The most commonly used model system for studying cDC in humans is that of the monocyte-derived dendritic cells (MDDC), which are obtained by culturing peripheral blood monocytes in the presence of GM-CSF and IL-4 for

Development of pDC

Recent studies carried out in mice have begun to illuminate the transcriptional requirements for development of subsets of DC. For example, Ozato and coworkers studied mice singly or doubly knocked-out for the transcription factors IRF-4 and IRF-8 [29]. Mice that lacked both of these transcription factors were devoid of both pDC and cDC. Reintroduction of the IRF-4 and IRF-8 restored normal development of both DC subsets. For pDC development, IRF-8, and to a lesser extent, IRF-4 were found by

Type I and type III IFNs

pDC are best known for their extraordinary ability to secrete high levels of IFN-α in response to many DNA and RNA viruses as well as synthetic TLR9 and TLR7 agonists. In fact, it has been reported that the type I and type III (discussed below) IFNs account for 60% of the genes expressed in activated pDC [31]. In addition to producing large quantities of IFN-α (as much as 3–10 pg/cell in response to a strong stimulus such as HSV-1), pDC also produce IFN-β (but at much lower levels relative to

Production of IFN-α by pDC

Although many cell types of both hematopoetic and non-hematopoietic origin have the capacity to produce IFN-α, pDC have been described as the “professional” IFN producing cells due to their ability to produce 10–100 times more type I IFN than other cell types. What makes these cells such exquisite producers of IFN-α is of great interest. Although signaling pathways for the induction of IFN-α have been well-studied, most of these pathways were worked out in model cell systems, not in pDC.

pDC at the interface of innate and adaptive immunity

Dendritic cells, including pDC, are uniquely poised at the interface of innate and adaptive immunity. While many cell types in the body are able to produce type I IFNs, the majority of these cells require viral gene expression before they are recognized by intracellular sensors. The ability of pDC to produce IFN-α in response to inactivated viruses or viral nucleic acids in the absence of replication has a clear advantage: many viruses have the ability to block IFN-α production in the cells

pDC in immune defense and autoimmunity

As described above, pDC, through their production of IFN-α and other cytokines, as well as through cell-contact-dependent mechanisms, have the ability to interact with multiple components of the innate and adaptive immune responses. Immature pDC are present in the blood, bone marrow and secondary lymphoid organs and can be recruited under stimulatory conditions to diverse areas in the body including (but not limited to) the skin, the cerebrospinal fluid, the synovium, the gut, the vaginal

Conclusions and perspectives

The fields of IFN and pDC biology have come an enormous distance since their initial beginnings a half century ago. The type I IFNs are now recognized as having key roles in the immune response – both to the host's benefit and harm – as well as for their virus “interference” first described by Isaacs and Lindenmann. Likewise, the obscure cells described by Lennert and Remmele have moved from plasma-like cells to natural IFN-producing cells to pDC and are now recognized as central players in the

Acknowledgements

This work is supported in part by research grant NIH NIAID AI26806 and a grant from the NJMS – University Hospital Cancer Center to PFB. Dr. Dai was supported by an NRSA post-doctoral fellowship at the Univ. of Pennsylvania School of Medicine.

Patricia Fitzgerald-Bocarsly, Ph.D. is a Professor of Pathology at the UMDNJ – New Jersey Medical School. Her work focuses on characterization of human pDC and their dysfunction in HIV-1 infection. Her laboratory has been studying human NIPC/pDC for more than 20 years and has made seminal contributions into the identity of these cells and their role in HIV-1 infection. Dr. Fitzgerald-Bocarsly is a recent section editor for the Journal of Immunology and is on the editorial board of Clinical

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    Patricia Fitzgerald-Bocarsly, Ph.D. is a Professor of Pathology at the UMDNJ – New Jersey Medical School. Her work focuses on characterization of human pDC and their dysfunction in HIV-1 infection. Her laboratory has been studying human NIPC/pDC for more than 20 years and has made seminal contributions into the identity of these cells and their role in HIV-1 infection. Dr. Fitzgerald-Bocarsly is a recent section editor for the Journal of Immunology and is on the editorial board of Clinical Immunology. She also serves on the NIH AIDS Immunology and Pathogenesis and AHA Microbiology and Immunology Study Sections.

    Jihong Dai, M.D., Ph.D. carried out post-doctoral work in the laboratory of Patricia Fitzgerald-Bocarsly at NJMS, then was a recipient of an NRSA post-doctoral fellowship at the University of Pennsylvania. She recently joined as a scientist at Humigen, the Institute for Genetic Immunology in New Jersey. Her main research interest is the susceptibility of human primary cells to HIV-1 infection.

    Sukhwinder Singh, Ph.D. is currently a post-doctoral fellow in the laboratory of Dr. Fitzgerald-Bocarsly at the UMDNJ – New Jersey Medical School. He previously held a pre-doctoral fellowship from the New Jersey Commission on Cancer Research. His current research interest is in understand the role of pDC in cross-presentation of antigens.

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