Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells

Laura J. Pallett, Upkar S. Gill, Alberto Quaglia, Linda V. Sinclair, Maria Jover-Cobos, Anna Schurich, Kasha P. Singh, Niclas Thomas, Abhishek Das, Antony Chen, Giuseppe Fusai, Antonio Bertoletti, Doreen A. Cantrell, Patrick T. Kennedy, Nathan A. Davies, Muzlifah Haniffa, Mala K. Maini (Lead / Corresponding author)

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    125 Citations (Scopus)

    Abstract

    Infection with hepatitis B virus (HBV) results in disparate degrees of tissue injury: the virus can either replicate without pathological consequences or trigger immune-mediated necroinflammatory liver damage. We investigated the potential for myeloid-derived suppressor cells (MDSCs) to suppress T cell-mediated immunopathology in this setting. Granulocytic MDSCs (gMDSCs) expanded transiently in acute resolving HBV, decreasing in frequency prior to peak hepatic injury. In persistent infection, arginase-expressing gMDSCs (and circulating arginase) increased most in disease phases characterized by HBV replication without immunopathology, whilst L-arginine decreased. gMDSCs expressed liver-homing chemokine receptors and accumulated in the liver, their expansion supported by hepatic stellate cells. We provide in vitro and ex vivo evidence that gMDSCs potently inhibited T cells in a partially arginase-dependent manner. L-arginine-deprived T cells upregulated system L amino acid transporters to increase uptake of essential nutrients and attempt metabolic reprogramming. These data demonstrate the capacity of expanded arginase-expressing gMDSCs to regulate liver immunopathology in HBV infection.

    Original languageEnglish
    Pages (from-to)591-600
    Number of pages10
    JournalNature Medicine
    Volume21
    Issue number6
    Early online date11 May 2015
    DOIs
    Publication statusPublished - 11 May 2015

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    Pallett, L. J., Gill, U. S., Quaglia, A., Sinclair, L. V., Jover-Cobos, M., Schurich, A., Singh, K. P., Thomas, N., Das, A., Chen, A., Fusai, G., Bertoletti, A., Cantrell, D. A., Kennedy, P. T., Davies, N. A., Haniffa, M., & Maini, M. K. (2015). Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells. Nature Medicine, 21(6), 591-600. https://doi.org/10.1038/nm.3856