Enhanced cytokine responsiveness in natural killer cells from a pilot cohort of uninfected seronegative women exposed to hepatitis C virus contaminated anti-D immunoglobulin

Background: Some people exposed to hepatitis C virus (HCV) appear to be capable of preventing infection in the absence of detectable antibody responses. These 9exposed seronegative (ESN)9 people appear naturally resistant to HCV infection. Here, we aimed to examine innate immune mechanisms in ESN individuals amongst rhesus negative Irish women exposed to HCV via contaminated anti-D immunoglobulin between 1977-79 and 1991-94. Methods: A total of 16 ESN individuals were recruited, along with 9 age- and gender-matched healthy controls. All tested negative for HCV-specific antibodies using conventional diagnostic assays. Peripheral blood cells were analysed for presence of adaptive immune response markers, innate immune responsiveness and natural killer cell phenotype and function. Results: The innate immune cell profile of ESN women in the present study was characterised by a significant decrease in monocyte frequency and elevated levels of interleukin-8 and -18 compared to age- and gender-matched healthy controls. NK cells from ESN women had normal expression of NK cell receptors but increased IFNγ-production upon cytokine and target cell stimulation as well as enhanced natural killer (NK) cell STAT3 phosphorylation in response to Type I IFN. Conclusions: We describe for the first time ESN individuals amongst Irish women with past exposure to HCV via contaminated anti-D immunoglobulin. NK cells from these ESN individuals are more responsive to cytokine signalling compared with age- and gender-matched controls. Human ESN cohorts can provide unique insights into the biological mechanisms associated with antigen-independent natural resistance to viral infection.