Pallett, L; (2014) Metabolic regulation of hepatic immunopathology by myeloid-derived suppressor cells. Doctoral thesis , UCL (University College London).

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Abstract

The liver provides a highly immunotolerant environment, that is exploited by hepatotropic viruses such as Hepatitis B virus (HBV), which establishes persistent infection in more than 350 million people worldwide. In this thesis the potential for myeloid-derived suppressor cells (MDSC) to exert metabolic regulation in this setting has been investigated. We found a mean approximate 9-fold expansion of granulocytic MDSC (gMDSC) in patients with chronic HBV infection (CHB) compared to uninfected, healthy controls (p<0.001). The most striking increases were seen in patients replicating HBV in the absence of immunopathology (p<0.01). gMDSC expressed high levels of the chemokine receptor, CXCR1, providing the potential for them to be chemoattracted by liver-derived interleukin-8 (IL-8); consistent with this, they were further enriched in the intrahepatic compartment. gMDSC from patients with CHB expressed increased amounts of arginase I, correlating with an increase in serum levels of this enzyme (p<0.01). Arginase I metabolises the conditionally essential amino acid L-arginine that is required for proliferating T cells; in line with this was an observed decrease in circulating L-arginine, particularly in those patients without liver inflammation. Liver pathology in CHB is ampli ed by the recruitment and activation of bystander (non-HBV-speci c) T cells; therefore the potential of gMDSC to down-regulate such responses was explored. Puri ed gMDSC from patients with CHB potently inhibit the expansion of bystander T cells capable of producing pro-inflammatory cytokines or mediating cytotoxicity. This inhibition was blocked using an arginase I-specific inhibitor, N-hydroxy-nor-arginine (nor-NOHA). Taken together, these data demonstrate the capacity for expanded arginase I expressing gMDSC to regulate liver immunopathology in CHB by depriving T cells of L-arginine.

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