February 19, 2008

Of viruses, tolls, TREMS and interferons
RIKEN researchers expand our understanding of how the immune system produces
specific antiviral proteins in response to viral infections.
The human body's defense against viruses is complex and much remains poorlyunderstood. More light has now been shed on this enigmatic field by researchers fromRIKEN's Research Center for Allergy and Immunology that they have identified a newcell surface protein critical to the antiviral response. The RIKEN team has characterized
how this new player works in concert with a network of other proteins to quickly boost
the production of extremely potent antiviral agents called interferons (IFNs).
The IFNs comprise a variable group of proteins that are generally only produced upon
immune system activation. IFNs are part of the immune system's non-specific response
and therefore represent the earliest defenses mounted against any invading viralpathogens, long before more specific immune reactions can be marshaled. The maintypes of human IFNs are classified as either Type 1 or Type 2 IFNs; IFN-a and IFN-b themost common Type 1 IFNs, are produced by virus-infected cells, and are very effectiveat protecting other cells from infection by reducing viral multiplication.
Although IFNs are often defined by their antiviral activities, many of these proteins are
multifunctional. Indeed, the effects of IFNs extend beyond immunomodulatory
consequences to encompass a wider spectrum of hormone-like activities and possibly
even anti-inflammatory mediation. Among the most prolific producers of IFNs are
dendritic cells (DCs), which are a specialized type of immune system cell.
Since DCs are the key orchestrators of an activated, specifically 'customized' and hence
delayed immune response, it is somewhat paradoxical that they also produce IFNs, thenon-specific, generic elements of early responses. Of the distinct DC subpopulations
that have been identified, plasmacytoid DCs (PDCs) typically produce the highest Type
1 IFN quantities when exposed to viruses.
PDCs are known to respond to external stimuli through 'toll-like receptors' (TLRs), cellsurface proteins that are one of the critical elements of the PDC-IFN activation pathway.
When a specific molecule that can stimulate an immune response docks in a TLR, ittriggers a signaling cascade of secondary events, which include signals mediated byother proteins called type 1 IFN-a/b receptors (IFNARs). Because TLR activity alone
cannot explain how these events collectively generate optimal IFN production, theRIKEN researchers focused on searching for new players in this IFN activation pathway.
The researchers used 'proteomics' - studying proteins on a large scale - to identify anew cell surface receptor they designated 'PDC-TREM' that allows PDCs to produce
amplified IFN levels. By examining spleen cells from normal and genetically modified
mice strains, the authors determined that PDC-TREM is unique among PDC-specificmolecules in that its surface expression is inducible - requiring both TLR- andIFNAR-signaling - and it cannot be detected on unstimulated PDCs.
The scientists also elaborated roles for several other proteins - PlxnA1, Sema6D,
DAP12 - that either form active complexes with PDC-TREM or induce its expression.
The authors studied changes during IFN production in the concentrations of these newelements of the PDC-IFN activation pathway and were able to delineate how thisPDC-TREM-mediated signaling cascade drives appropriate, measured responses
between various effector proteins and their downstream targets, although much remains
to be elucidated. Crucially, the RIKEN's group illustrated that interfering with or
disrupting PDC-TREM expression and/or activity severely inhibited the signaling
process and IFN production. Their work has clearly demonstrated that PDC-TREM is
intimately involved with the augmented IFN production that characterizes PDCs.
Since viruses often evolve sophisticated mechanisms to overcome IFN-mediatedreactions, the RIKEN team's findings should help us to understand enough about IFN
biology to hopefully keep viral scourges at bay.
Original work:
Watarai, H., Sekine, E., Inoue, S., Nakagawa, R., Kaisho, T., Taniguchi, M.
PDC-TREM, a plasmacytoid dendritic cell-specific receptor, is responsible foraugmented production of type I interferon, PNAS, published online on Feb. 18, 2008

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