Research paperDendritic cells—At the front-line of pathogen attack
Introduction
Initiation of protective immune defences against a particular pathogen requires that the pathogen be processed efficiently by the immune system. Central to this efficacy is the role played by the monocytic cell family, in particular the dendritic cell (DC) (Banchereau and Steinman, 1998). This is also observed with vaccination (for example see the reviews of Janeway, 1989, Fearon, 1997). Vaccine efficacy is often assured through the application of adjuvants. While the vaccine itself provides the antigen against which the adaptive immune defences will develop their specific immunity, the adjuvant provides the means of initiating the innate defence response. The characteristics of these innate responses determine the ultimate value of the adaptive responses, and therefore the overall efficiency of the immune defence.
Clearly, the efficiency of immune response and defence against pathogens is dependent on the role played by DC. However, not all in the DC sphere of influence will promote immune defence, nor is that desired when considering that immune responses must also be correctly controlled to prevent over-activation of the defences. Furthermore, the immune system does not have everything its own way. Nature is continually confronting us with new challenges to immune defence development and protection of the host. It is important to consider that nature has one dominant characteristic – chaos – ensuring that the most successful of hosts and pathogens will continue to survive.
In this review, we will look at the complexity of the DC sphere of influence, but focusing on the DC family. However, this is not a review of the porcine DC family per se, which is the subject of an upcoming review (Summerfield and McCullough, 2008). Their importance will be highlighted in terms of how pathogens have adapted processes of immune evasion, focusing on two viral examples of the diversity operating in nature for pathogen obstruction of immune defence operation. While the review will present our current understanding of the porcine DC family and virus infections therein, reference will also be made to knowledge obtained from other species – in particular the mouse – which is helping our insight into the battle between the immune defence and the pathogen infection. The aim of the review is not to analyse comparatively DCs from different species – this is to be published elsewhere (Dawson et al., 2008) – but to provide examples of how viral pathogens vary mechanistically in their modulation of DC responsiveness. Therein, it is impossible to provide an exhaustive review of all viruses capable of modulating DCs, for which reason the review concentrates on two examples, one an RNA virus (classical swine fever virus, CSFV) and the other a DNA virus (porcine circovirus) showing very different mechanisms of immunomodulation.
Section snippets
The critical role of dendritic cells
DCs are a heterogenous group of leukocytes, but can be roughly divided into two major groups: conventional DC (cDC) with their main function in antigen presentation; plasmacytoid DC (pDC) – also called natural interferon producing cells (NIPC or IPC) – with their main function being the production of type I IFN. These DC subsets have been described in a number of species (Wu and Dakic, 2004), including the pig (Summerfield et al., 2003, Guzylack-Piriou et al., 2004). The DC is crucial in the
Maturation and activation of dendritic cells
The review by Gogolák et al. (2003) highlights the importance of these maturation events for the cDC to advance efficacious immune defences. Studies on porcine DC (Summerfield et al., 2003, Guzylack-Piriou et al., 2004, Guzylack-Piriou et al., 2006; McCullough and Summerfield, unpublished data), relating to those on murine DC (reviewed by Amyere et al., 2002), have identified particular characteristics of immature and mature cDC. The immature cDC can be characterized as having relatively high
Dendritic cell maturation—the importance of the pDC
The pDCs are the major producers of Type I IFN in the immune system, and are the most efficient at responding to nucleic acid-based PAMPs—this has been observed with porcine DC (Summerfield et al., 2003, Guzylack-Piriou et al., 2004) as well as with murine and human cells (Seeds et al., 2006). These cells also respond to viruses via surface PRRs, as seen with porcine pDC responding to TGE virus (Guzylack-Piriou et al., 2004). The Type I IFN production by pDC has a particularly important role in
Perpetrators of chaos—virus modulation of DC function
Despite the capacity of the immune defences to provide effective defence against pathogen attack, the host does not have everything its own way. A number of viral pathogens can infect cells of the immune system – particularly DC and macrophages – reducing or even impairing the host's capacity for immune defence. While the virus infections can be visualised in vivo with respect to the preponderance of DC and macrophages carrying virus antigen and genomic material, the immunomodulatory
Conclusions
Overall, it is clear that DCs (cDC and pDC) represent a critical central element in the efficient functioning of immune defence generation and maintenance. During their evolution, viruses have developed an array of different processes to evade detection and/or destruction by the innate defences. This differs for different viruses, and also varies dependent on whether the cDCs or pDCs are involved. However, with the interdependence of the DC subpopulations, viral interference with one will have
Conflict of interest
None.
Acknowledgements
The work presented in this review has been supported by project grants awarded by the European Union – EU Project SSPE-CT-2004-513928, EU Project SSPE-CT-2003-503603, EU Project QLK2-CT-2002-00825, EU Project QLK2-2001-01374, EU Project QLK2-CT-2001-01346, EU Project QLK2-1999-00445, EU FP4 Project FAIR5-PL97- 3732 – and the Swiss Federal Veterinary Office.
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