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

Lookup NU author(s): Professor Muzlifah Haniffa

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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.

Publication metadata

Author(s): 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

Publication type: Article

Publication status: Published

Journal: Nature Medicine

Year: 2015

Volume: 21

Issue: 6

Pages: 591-600

Print publication date: 01/06/2015

Online publication date: 11/05/2015

Acceptance date: 31/03/2015

ISSN (print): 1078-8956

ISSN (electronic): 1546-170X

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/nm.3856

DOI: 10.1038/nm.3856

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