Das, A. (2009) Constraints on the CD8 T cell response in chronic HBV infection. Doctoral thesis, UCL (University College London).
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The inflamed liver in chronic hepatitis B virus infection (CHB) is characterised by a large influx of non-virus specific CD8 T cells, which we hypothesize could provide insights into mechanisms of failure of viral control and liver damage in this setting. We compared the effector function of total circulating and intrahepatic CD8 T cells in CHB patients and healthy donors. We demonstrated that CD8 T cells from CHB patients, regardless of their antigen specificity, were impaired in their ability to produce IL-2 and proliferate upon TCR dependent stimulation. By contrast, these CD8 T cells had preserved production of the proinflammatory cytokines IFN-γ and TNF-α. We provide evidence that this global CD8 T cell impairment of IL-2 production and proliferation may be partially attributable to a) downregulation of the proximal TCR signalling molecule CD3ζ (zeta), secondary to L-arginine depletion within the inflamed hepatic microenvironment and b) exhaustion of CD8 T cells associated with a terminally differentiated phenotype and shortened telomeres following long-term exposure to high level viraemia. In addition, we implicate IL-10 as a regulatory cytokine in CHB, and show preferential suppression of HBV-specific CD8 T cells compared to responses for other viruses by IL- 10 blocking experiments. Circulating IL-10 levels were elevated in patients and correlated temporally with viral load and ALT (surrogate marker of liver inflammation) during spontaneous flares of CHB. B cells were shown to be a potent source of this cytokine upon CpG stimulation, and these ‘regulatory’ cells, identified as CD24 high CD38 high transitional, were selectively enriched in CHB and correlated with disease flares. Depletion of this subset rescued HBV-specific responses, implicating a pathogenic role in suppressing T cell function and viral persistence in this setting. Collectively, our data imply that impairment of CD8 T cell function during CHB is likely multifactorial, and that these polarised CD8 T cells may then both impede viral control, whilst contributing to the pro-inflammatory cytokine environment.
|Title:||Constraints on the CD8 T cell response in chronic HBV infection|
|Open access status:||An open access version is available from UCL Discovery|
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