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Mary van Helden

Tuesday 4 October 2011

Cellular immune responses to respiratory viruses

Promotor: Prof. dr W. van Eden
Defence: 4 October 2011
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Summary
In this thesis we have used mice models to study fundamental aspects of innate and adaptive immune responses to respiratory virus infections.

In Chapter 2 we studied NK cell migration and proliferation in response to respiratory virus infection. We found that despite a dramatic increase in quantities of NK cells at the site of infection, only a number of NK cells proliferated in the airways or draining lymph node. Instead, we found that upon respiratory virus infection, NK cells migrated in a CCR2-mediated fashion to the site of infection, while they proliferated in the spleen and BM. We therefore postulate that in response to respiratory virus infection, NK cells migrate from internal compartments to the airways, in a CCR2-dependent fashion, which in turn induces proliferation and replenishment of NK cells in the central compartments.

In Chapter 3 we studied fundamental characteristics of long-lived NK cells of respiratory virus infected mice. We found that adoptively transferred NK cells survived for a remarkably long time in recipient mice, regardless whether they originated from naïve or respiratory virus infected donor mice. Long-lived NK cells had a mature phenotype and underwent homeostatic proliferation in the BM. In addition, respiratory virus infection induced antigen-aspecific proliferation of these long-lived NK cells in the BM. Thus our results show that long-lived NK cells migrate to the BM where they undergo homeostatic and infection-induced proliferation.

Comparing NK cell kinetics in the airways of PVM and influenza virus infected mice we showed in Chapter 4, that NK cell responses were delayed after PVM infection. In addition, compared to influenza virus infected mice, we found a massive influx of CD8 T cells in the lungs of PVM infected mice. Early activation of the innate immune system following PVM infection, obtained by co-infection with RSV provided protection against PVM-induced illness. PVM-specific CD8 T cell, induced by prior vaccination or adoptively transferred, reduced weight loss and pathology. We therefore postulate that the early delay in innate immune responses in PVM infected mice results in uncontrolled viral replication and consequently in T-cell induced pathology. Early viral control by the innate immune system or memory CD8 T cells diminishes the viral load at later time points, and therewith PVM associated pathology.

By generating mice that lack both PA28 and immunosubunits β5i/LMP7 and β2i/MECL-1, we studied the potentially compounded role of these cytokine-inducible proteasome components in Chapter 5. By measuring MHC class I cell surface levels, we showed that mice lacking both PA28 and immunoproteasome subunits display lower MHC class I cell surface levels then mice lacking either PA28 or immunoproteasome subunits. We therefore conclude that PA28 and the immunosubunits have additive roles in the generation of peptides that bind to MHC class I molecules, suggesting that they use fundamentally different mechanisms to enhance 20S proteasome mediated generation of MHC calss I ligands.

In chapter 6 we first studied whether the lower MHC class I expression on cells of immunoproteasome-deficient mice influenced NK cell education, and found that these mice had normally responsive NK cells in the periphery. Second, we studied whether immunoproteasome-deficient cells were targeted for NK cell-mediated killing. We showed that adoptively transferred immunoproteasome-deficient cells were tolerized by naïve recipients, while influenza virus infection induced NK cell-mediated rejection of these transferred cells. Thus, we here show for the first time, that infection can induce NK cell-dependent rejection of an otherwise tolerated graft.

In summary, our findings have furthered our knowledge of the dynamics of NK cell responses during respiratory virus infections and their potential to become long-lived cells. Our studies contribute to our understanding of virus-host interactions during PVM infection in mouse models. Finally, our results increase our knowledge of fundamental aspects of NK cell-mediated killing, which helps to understand the 'indirect' role of immunoproteasomes in 'tolerance versus reject' decisions by NK cells in transplanted hosts.

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