Plasmacytoid dendritic cells and type I IFN: 50 years of convergent history
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
References (136)
- et al.
The role of type I interferon production by dendritic cells in host defense
Biochimie
(2007) - et al.
Plasmacytoid dendritic cells activate lymphoid-specific genetic programs irrespective of their cellular origin
Immunity
(2004) A close developmental relationship between the lymphoid and myeloid lineages
Trends Immunol
(2006)- et al.
Ikaros is required for plasmacytoid dendritic cell differentiation
Blood
(2006) - et al.
Specialization, kinetics, and repertoire of type 1 interferon responses by human plasmacytoid predendritic cells
Blood
(2006) - et al.
Viral infections activate types I and III interferon genes through a common mechanism
J Biol Chem
(2007) - et al.
Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6
Immunity
(2003) Isolation and characterization of plasmacytoid dendritic cells from Flt3 ligand and granulocyte-macrophage colony-stimulating factor-treated mice
Blood
(2001)- et al.
Differential migration behavior and chemokine production by myeloid and plasmacytoid dendritic cells
Hum Immunol
(2002) - et al.
Opposing roles of blood myeloid and plasmacytoid dendritic cells in HIV-1 infection of T cells: transmission facilitation versus replication inhibition
Blood
(2006)
Detection of HBD1 peptide in peripheral blood mononuclear cell subpopulations by intracellular flow cytometry
Peptides
Identification of a leukemic counterpart of the plasmacytoid dendritic cells
Blood
Viral induction of low frequency interferon-alpha producing cells
Virology
Antibody-dependent induction of type 1 interferons by poliovirus in mononuclear blood cells reuires the type II Fcγ receptor (CD32)
Virol
Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and resiquimod
Cell Immunol
Interferon induction by HIV glycoprotein 120: role of the V3 loop
Virology
Induction of interferon-α by glycoprotein D of herpes simplex virus: a possible role of chemokine receptors
Virology
Siglec-H is an IPC-specific receptor that modulates type I IFN secretion through DAP12
Blood
Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-alpha/beta gene induction
Immunity
Spontaneous formation of nucleic acid-based nanoparticles is responsible for high interferon-alpha induction by CpG-A in plasmacytoid dendritic cells
J Biol Chem
Two discrete promoters regulate the alternatively spliced human interferon regulatory factor-5 isoforms. Multiple isoforms with distinct cell type-specific expression, localization, regulation, and function
J Biol Chem
Virus-induced heterodimer formation between IRF-5 and IRF-7 modulates assembly of the IFNA enhanceosome in vivo and transcriptional activity of IFNA genes
J Biol Chem
Recognition of cytosolic DNA activates an IRF3-dependent innate immune response
Immunity
Herpes simplex virus type 1 activates murine natural interferon-producing cells through toll-like receptor 9
Blood
The interferon response circuit: induction and suppression by pathogenic viruses
Virology
Virus interference. 1. The interferon
Proc R Soc Biol
Role of interferon in natural kill of HSV-1 infected fibroblasts
J Immunol
Anti-viral activity induced by culturing lymphocytes with tumor derived or virus-transformed cells. Identification of the anti-viral activity as interferon and characterization of the human effector lymphocyte subpopulation
J Exp Med
Monocyte is the main producer of human leukocyte alpha interferons following Sendai virus induction
Prog Med Virol
A leukocyte subset bearing HLA-DR antigens is responsible for in vitro alpha interferon production in response to viruses
Nat Immun Cell-Growth Regul
Properties of human natural interferon-producing cells stimulated by tumor cell lines
Eur J Immunol
Independence of interferon production and natural killer function and association with opportunistic infection in acquired immune deficiency syndrome
Human mononuclear cells which produce interferon-alpha during NK (HSV-FS) assays are HLA-DR positive cells distinct from cytolytic natural killer effectors
J Leukocyte Biol
The mannose receptor mediates induction of IFN-alpha in peripheral blood dendritic cells by enveloped RNA and DNA viruses
J Immunol
Sequential enrichment and immunocytochemical visualization of human interferon-α producing cells
J Interferon Res
CD4+ blood dendritic cells are potent producers of IFN-α in response to in vitro HIV-1 infection
J Immunol
Dendritic cells and IFN-a producing cells are two functionally distinct non-B, non-monocytic HLA-DR+ cell subsets in human peripheral blood
Immunology
Karyometrische untersuchungen an lymphknotenzell des menschen. I. Mitt germinoblasten, lymphoblasten und lymphozyten
Acta Haematol
Natural interferon producing cells: the plasmacytoid dendritic cells
Biotechniques
Plasmacytoid T cells. Immunohistochemical evidence for their monocyte/macrophage origin
Am J Pathol
The enigmatic plasmacytoid T cells develop into dendritic cells with interleukin-3 and CD40 ligand
J Exp Med
Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon
Nat Med
The nature of the principal type 1 interferon-producing cells in human blood
Science
IkappaB kinase-alpha is critical for interferon-alpha production induced by Toll-like receptors 7 and 9
Nature
Dendritic cell ontogeny: a human dendritic cell lineage of myeloid origin
Proc Natl Acad Sci USA
The lymphoid past of mouse plasmacytoid cells and thymic dendritic cells
J Immunol
Id2 and Id3 inhibit development of CD34(+) stem cells into predendritic cell (pre-DC)2 but not into pre-DC1. Evidence for a lymphoid origin of pre-DC2
J Exp Med
Viral infection switches non-plasmacytoid dendritic cells into high interferon producers
Nature
Bone marrow plasmacytoid dendritic cells can differentiate into myeloid dendritic cells upon virus infection
Nat Immunol
Are dendritic cells afraid of commitment?
Nat Immunol
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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.