A role for type 111 interferons in the natural killer cell immune response to virus

Abstract

Natural Killer (NK) cells are fundamental effector cells of the innate immune system that function to eliminate virally infected and transformed cells. One key way in which they do this is through the production of cytokines, of which the interferons (IFNs) are particularly important in carrying out anti-viral effects. Hepatitis C (HCV) is a virus found worldwide and in the majority of cases, leads to chronic infection and liver damage. Recent evidence supports a role for the innate immune system in HCV clearance as innate immune genes, in particular the NK cell gene KIR2DS3 and the recently reported IL28B (IFN-λ3) SNP, have been shown to contribute to disease progression. Research carried out for this thesis investigated whether the novel family of IFN-λs contributed to the established role for NK cells in immunity to viral infection. We investigated the response of human sorted NK cells to poly I:C, a known inducer of lFN-λ. We have demonstrated a direct effect of poly I:C on human NK cells and, although changes in IFN-A. gene expression were detected, we suggest that NK cells are not the main producers of IFN-λ. We also assessed the effect of type III IFNs on human NK cells. None of the three 1FN-λ family members activated NK cells. However IL28A and IL28B inhibited IFN-y production by NK cells of some healthy and HCV infected donors. This therefore supports a functional link between NK cells and type III IFN. In addition we have shown IFN-λ production is impaired in PBMCs from HCV infected patients, an observation that is further supported by decreased levels of IFN-λ in the serum of HCV infected patients. Our findings contribute to recent evidence suggesting that lFN-λ plays a role in the immune response to HCV and finds a functional link between NK cells and IFN-λ cytokines.