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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Acknowledgements
This work was funded by UK Medical Research Council grant G0801213 to M.K.M., a UK Medical Research Council studentship to L.J.P., Medical Research Council/AStar grant G0901374 to M.K.M. and A.B., a Wellcome Trust Senior Investigator Award (no. 101849/Z/13/Z) to M.K.M., a National Health and Medical Research Council Postgraduate Research Scholarship to K.P.S., a Wellcome Trust grant 097418/Z/11/Z to D.A.C. and The London Charity (723/1795) to P.T.K. We thank P. Kropf for advice on the assessment of gMDSC arginase I release, R. Milne, E. Nastouli, and the Clinical Virology Departments at University College Hospital and the Royal Free Hospital for CMV serology and HBsAg quantification, and O. Pop and C. Starling for assistance with immunostaining. We are very grateful to all patients and control volunteers who participated in this study and to clinical staff who helped with participant recruitment and monitoring.
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L.J.P., A.B., M.H. and M.K.M. conceived the project; L.J.P., A.Q., L.V.S., M.J.-C., K.P.S., A.D., A.B., D.A.C., N.A.D., M.H. and M.K.M. designed the experiments; L.J.P., A.Q., L.V.S., M.J.-C., K.P.S., N.T., A.C. and M.H. generated data; L.J.P., U.S.G., A.Q., L.V.S., A.S., K.P.S., N.T., N.A.D. and M.K.M. analyzed data; U.S.G., G.F. and P.T.K. provided essential patient samples; L.J.P. and M.K.M. prepared the manuscript; U.S.G., A.Q., L.V.S., A.S., K.P.S., N.T., A.D., A.C., G.F., A.B., D.A.C., P.T.K., N.A.D. and M.H. provided critical review of the manuscript.
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M.K.M., P.T.K. and A.B. have carried out consultancy and participated in advisory boards and educational committees for the development of novel immunotherapeutic strategies for HBV for Bristol Myers Squibb, Gilead, Immune Targeting Systems, MedImmune, Roche, Transgene.
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Pallett, L., Gill, U., Quaglia, A. et al. Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells. Nat Med 21, 591–600 (2015). https://doi.org/10.1038/nm.3856
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DOI: https://doi.org/10.1038/nm.3856
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