Attenuated Antigen-specific T Cell Responses in Cirrhosis Are Accompanied by Elevated Serum Interleukin-10 Levels and Down-regulation of HLA-DR on Monocytes

Background: Advanced liver disease predisposes to bacterial translocation and endotoxaemia which can contribute to elevated circulating levels of IL-10 and down-regulation of MHC class II on antigen-presenting cells. We sought to evaluate antigen-specific T-cell responses toward common viral antigens in order to investigate defects in cellular immunity in cirrhosis.

Methods: Peripheral blood was obtained from 22 cirrhotic patients with systemic inflammation, 13 cirrhotic patients without systemic inflammation and 14 healthy controls. C-reactive protein was used as an indicator for systemic inflammation using a cut-off of 10 mg/l. Intracellular Th1 cytokines were quantified after T cell-stimulation with the viral peptides EBNA1 and BZLF1 or the bacterial superantigen SEB by flow cytometry. Serum levels of lipopolysaccharide-binding protein (LBP) and IL-10 were quantified by ELISA.

Results: Compared to healthy controls, patients with cirrhosis had higher circulating levels of LBP and IL-10, an expansion of peripheral blood CD14+ monocytes with low HLA-DR expression and an increased fraction of CD25-positive CD4+ and CD8+ T cells. These findings were most pronounced in cirrhotic patients with systemic inflammation but fell short of reaching statistical significance when comparing against cirrhotic patients without systemic inflammation. In the former group TNF-α production in CD4+ and CD8+ T cells was reduced after stimulation with SEB, whereas there was no significant difference between the total cohort of cirrhotic patients and controls. After stimulation with the overlapping peptide pools for viral antigens EBNA1 and BZLF1, the number of responding T cells and the amount of TNF-α or IFN-γ production did not differ between the three pre-defined groups. However, cirrhotic patients with null-responses to EBV peptides had significantly higher serum IL-10 levels than responders to EBV peptides. Furthermore, TNF-α production in responding T cells was attenuated in patients with a high frequency of CD14+ HLA-DR- monocytes.

Conclusion: Our data suggest that bacterial translocation, endotoxaemia, inflammation and T cell activation in cirrhosis are accompanied by an increase in circulating anti-inflammatory cytokines, reduced monocytic MHC class II expression and attenuated cytokine production in T cells. These changes are likely to contribute to altered adaptive immune responses during infection or after vaccination.