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)

    Research output: Contribution to journalArticle

    109 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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    Arginase
    Hepatitis B
    Viruses
    Liver
    T-cells
    Hepatitis B virus
    Arginine
    T-Lymphocytes
    Amino Acid Transport Systems
    Chemokine Receptors
    Hepatic Stellate Cells
    Nutrients
    Wounds and Injuries
    Virus Diseases
    Virus Replication
    Infection
    Myeloid-Derived Suppressor Cells
    Tissue
    Food

    Cite this

    Pallett, L. J., Gill, U. S., Quaglia, A., Sinclair, L. V., Jover-Cobos, M., Schurich, A., ... 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
    Pallett, Laura J. ; Gill, Upkar S. ; Quaglia, Alberto ; Sinclair, Linda V. ; Jover-Cobos, Maria ; Schurich, Anna ; Singh, Kasha P. ; Thomas, Niclas ; Das, Abhishek ; Chen, Antony ; Fusai, Giuseppe ; Bertoletti, Antonio ; Cantrell, Doreen A. ; Kennedy, Patrick T. ; Davies, Nathan A. ; Haniffa, Muzlifah ; Maini, Mala K. / Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells. In: Nature Medicine. 2015 ; Vol. 21, No. 6. pp. 591-600.
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    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.",
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    Pallett, LJ, Gill, US, Quaglia, A, Sinclair, LV, Jover-Cobos, M, Schurich, A, Singh, KP, Thomas, N, Das, A, Chen, A, Fusai, G, Bertoletti, A, Cantrell, DA, Kennedy, PT, Davies, NA, Haniffa, M & Maini, MK 2015, 'Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells', Nature Medicine, vol. 21, no. 6, pp. 591-600. https://doi.org/10.1038/nm.3856

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

    In: Nature Medicine, Vol. 21, No. 6, 11.05.2015, p. 591-600.

    Research output: Contribution to journalArticle

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    AU - Singh, Kasha P.

    AU - Thomas, Niclas

    AU - Das, Abhishek

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    AU - Fusai, Giuseppe

    AU - Bertoletti, Antonio

    AU - Cantrell, Doreen A.

    AU - Kennedy, Patrick T.

    AU - Davies, Nathan A.

    AU - Haniffa, Muzlifah

    AU - Maini, Mala K.

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    N2 - 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.

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    Pallett LJ, Gill US, Quaglia A, Sinclair LV, Jover-Cobos M, Schurich A et al. Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells. Nature Medicine. 2015 May 11;21(6):591-600. https://doi.org/10.1038/nm.3856