Research paper
Dendritic cells—At the front-line of pathogen attack

https://doi.org/10.1016/j.vetimm.2008.10.290Get rights and content

Abstract

Efficient immune defence function is dependent on the role played by dendritic cells (DCs), particularly the interaction between conventional DC (cDC) and plasmacytoid DC (pDC), together with other monocytic cells. This functionality of immune defences is open to manipulation by viral pathogens infecting DC, a situation further complicated by the diversity of mechanisms employed by different viruses and the subset of DC involved. The present review uses two virus examples – classical swine fever virus (CSFV) and porcine circovirus type 2 (PCV2) – to demonstrate the complexity of this host–pathogen scenario.

CSFV is a monocytotropic RNA virus infecting and replicating in both cDC and pDC. This virus employs its non-structural Npro protein for antagonizing the Type I interferon (IFN) induction pathway. The Npro protein promotes proteasomal degradation of interferon regulatory factor (IRF)3, particularly notable in cDC. In contrast, CSFV infection induces IFNα production by pDC, probably due to a lack of interference by the Npro protein with the IRF7 more prominent in pDC. Such ability of the virus to inhibit cDC while augmenting IFNα production by pDC might lead to an exaggerated pDC response, relating to the immunopathological characteristics of the disease.

PCV2 is an ssDNA containing virus, which in contrast to CSFV is inefficient in its capacity to replicate in DC. Recent evidence suggests that virus replication occurs in endothelial cells, with the DC being more involved through their particularly elevated endocytosis of the virus. PCV2 can accumulate to high levels both in vitro and in vivo, a phenomenon dependent on the virus capsid protein, inferring that the viral capsid or genome impedes DC endocytic degradation of the virus. Nevertheless, the presence of PCV2 in cDC does not interfere with processing of other antigens. The immunoregulatory characteristics of PCV2 are manifest as impairment of “danger” recognition by cells of the innate defences. This varies dependent on the “danger” signal and the cells responding, especially when one compares cDC and pDC. Overall, the PCV2-induced immunomodulation contrasts with that of CSFV in being a property dependent on the viral genome, particularly the dsDNA replicative form, and with immunoregulatory capacity for both cDC and pDC. Moreover, PCV2 compromises immune defence development against other pathogens rather than itself.

In conclusion, the DC family represents a critical immune defence element open to modulation by virus infection, with serious consequences for host resistance to disease. The characteristics of the immune modulation depend on the virus and the DC subsets involved. Overall, the roles played by the pDC can be decisive in shaping the outcome of the infection and the characteristics of the virus-induced immunocompromisation.

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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