Review
Interferon-producing cells: on the front line in immune responses against pathogens

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Abstract

Interferon-producing cells (IPC) constitute a small population of leukocytes that secrete high levels of type I interferons in response to viruses. Although human IPC have been known for almost two decades, murine IPC have been identified only recently. Furthermore, it has been shown that IPC correspond to the enigmatic ‘plasmacytoid cells’ identified in human lymph nodes during infections. These breakthroughs have brought IPC to the attention of immunologists for their role in innate immunity and in shaping T cell responses. Here we review recent progress and outstanding questions in the field.

Section snippets

Introduction: The IPC — an elusive cell with multiple identities

Interferon-producing cells (IPC) were originally identified in the 1980s as a small subset of human leukocytes specialized in the secretion of high levels of type I interferons (type I IFN, i.e. IFN-α, -β and -ω) in response to certain viruses 1., 2., 3.. Since these cells lacked all known lineage markers, their precise origin was unclear.

Almost simultaneously, pathologists identified a unique cell population that was particularly abundant in lymph nodes of patients with infectious diseases [4]

The controversial origin of IPC: do they cross lineage boundaries?

It is unclear whether IPC derive from a myeloid or lymphoid progenitor. In agreement with a myeloid origin, IPC have been obtained in vitro in the presence of IL-3 from CD34+ progenitors that also express the receptor for M-CSF (macrophage-colony-stimulating factor) [10]. In addition, plasmacytoid tumor proliferations are associated with acute or chronic myelomonocytic leukemias 11., 12..

On the other hand, several observations support a lymphoid origin of IPC. IPC lack typical myeloid markers,

The response of IPC to selected microbial products correlates with the expression of certain TLR

IPC have been recently compared with DC for their ability to respond to a variety of microbial products. CpG oligonucleotides — which mimic bacterial DNA — promote production of type I IFN by IPC, but have no effect on myeloid DC 19., 20., 21., 22.. On the other hand, lipopolysaccharide (LPS) or poly (I:C) — which mimics viral double-stranded RNA — induce production of type I IFN by myeloid DC 23., 24., but have no effect on IPC (Fig. 1). There is now evidence that these diversified responses

From the blood to lymph nodes: the migration route of IPC

Human IPC have been found predominantly in the blood and in secondary lymphoid organs 4., 5., whereas only few studies have reported IPC in skin and mucosae 35., 36., 37.. Typically, IPC are located around the postcapillary high endothelial venules (HEV) of peripheral lymph nodes. IPC are particularly abundant in lymph nodes affected by infections or other inflammatory conditions. This anatomical localization has suggested that IPC may enter lymph nodes from the blood, through HEV, during

The long-sought identification of murine IPC

Although human IPC have been known for almost two decades, the existence of murine IPC was mysterious until recently. Trinchieri and colleagues have now identified them within the Gr-1+ fraction of splenocytes [39••]. Murine IPC have a plasma-cell-like morphology, express CD11c, Gr-1 and B220 but lack CD11b. Two additional studies have reported similar findings 40••., 41••..

Following viral infections in vivo or incubation with CpG or viruses in vitro, murine IPC produce type I IFN and IL-12 and

The function of IPC in linking innate and adaptive immunity

IPC have been shown to be the most potent producers of type I IFN 2., 3., 8., 9., perhaps because of a unique transcriptional regulation of type I IFN genes [42]. In the mouse, IPC-mediated production of type I IFN is critical for the control of murine cytomegalovirus (MCMV) infection, but not of lymphochoriomeningitis virus (LCMV) infection, indicating that IPC react only to certain pathogens [43••].

IPC-secreted type I IFN are also important in inducing Th1 polarization of human T helper cells

Are IPC professional antigen-presenting cells?

There is some evidence that IPC could further contribute to adaptive responses by capturing antigens in the periphery or in the blood and presenting them to T cells in the lymph nodes. IPC selectively express a novel C-type-lectin receptor, called BDCA-2, which may function as an antigen-capturing molecule [51•]. In addition, it has been shown that, upon encountering certain stimuli, IPC undergo a process of maturation that resembles that observed in myeloid DC. This process involves increased

Can IPC protect from HIV infection and tumors?

Although the role of type I IFN in protecting the host from viral infection is well established, it is unclear whether this is relevant to the pathogenesis of HIV. IPC express CD4 and the HIV coreceptors CXCR4 and CCR5. Indeed, recent reports have shown that HIV infects IPC and, paradoxically, replicates more efficiently in IPC than in myeloid DC, despite the ability of IPC to make type I IFN [52]. Lower numbers of IPC and loss of IPC function have been observed in the peripheral blood of

Too much of a good thing: IPC and autoimmune diseases

It has been known for some time that long-term treatment of patients affected by viral infections with IFN-α promotes development of autoantibodies and autoimmune syndromes. There is now evidence that chronic production of type I IFN by IPC may contribute to autoimmune diseases, such as systemic lupus erythematosus (SLE) [59]. Complexes of double-stranded (ds) DNA with anti-DNA antibodies, which are present in the serum of SLE patients, are potent inducers of IFN-α 60., 61., 62.. DNA–anti-DNA

Survival and growth of IPC

To study the physiology of IPC it is important to develop a procedure for the production of large amounts of these cells in vitro. Human IPC isolated from blood survive in vitro in the presence of IL-3 but do not proliferate. Interestingly, injection of FL or G-CSF (granulocyte-colony-stimulating factor) in healthy individuals results in a significant increase in blood IPC 48., 64., suggesting that FL and G-CSF can induce differentiation of IPC from a precursor cell. Indeed, in vitro culture of

Conclusions: IPC as secretory cells

IPC are emerging in innate immunity as a cell population specialized in secreting type I IFN and IL-12 in response to selected pathogens. Through release of cytokines, IPC control myeloid DC 43••., 63••., 68•., activate macrophages and NK cells, and induce Th1 polarization of T helper cells and expansion of regulatory T cells. The ongoing characterization of IPC is consistent with the idea that IPC are totally distinct from DC. The recent identification of murine IPC will allow confirmation of

Update

Recent work has demonstrated that IL-10-producing T cells are important in limiting inflammation 69., 70..

Acknowledgements

We would like to thank Tom Cirrito, Rich DiPaolo, Susan Gilfillan, Michelle Hurchla and Ravi Veeraswamy for reviewing the manuscript.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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