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

Nature Medicine volume 21, pages 591–600 (2015)Cite this article

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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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Figure 1: gMDSCs expand in subjects replicating HBV in the absence of immunopathology.
Figure 2: gMDSC frequencies are transiently induced in acute HBV infection and decline before acute and chronic hepatic flares.
Figure 3: Arginase+ gMDSC frequencies and circulating arginase I concentrations are higher and L-arginine levels are lower in subjects with HBV replication without immunopathology.
Figure 4: Accumulation of arginase+ gMDSCs in the liver.
Figure 5: gMDSCs suppress functional T cells in an arginase I–dependent manner.
Figure 6: Differential CD98 expression on T cells during CHB.

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References

  1. Guidotti, L.G. & Chisari, F.V. Immunobiology and pathogenesis of viral hepatitis. Annu. Rev. Pathol. 1, 23–61 (2006).

    Article  CAS  Google Scholar 

  2. Maini, M.K. et al. The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection. J. Exp. Med. 191, 1269–1280 (2000).

    Article  CAS  Google Scholar 

  3. Bertoletti, A. & Maini, M.K. Protection or damage: a dual role for the virus-specific cytotoxic T lymphocyte response in hepatitis B and C infection? Curr. Opin. Immunol. 12, 403–408 (2000).

    Article  CAS  Google Scholar 

  4. Kakimi, K. et al. Blocking chemokine responsive to gamma-2/interferon (IFN)-gamma inducible protein and monokine induced by IFN-gamma activity in vivo reduces the pathogenetic but not the antiviral potential of hepatitis B virus-specific cytotoxic T lymphocytes. J. Exp. Med. 194, 1755–1766 (2001).

    Article  CAS  Google Scholar 

  5. Sitia, G. et al. MMPs are required for recruitment of antigen-nonspecific mononuclear cells into the liver by CTLs. J. Clin. Invest. 113, 1158–1167 (2004).

    Article  CAS  Google Scholar 

  6. Das, A. et al. Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection. J. Exp. Med. 205, 2111–2124 (2008).

    Article  CAS  Google Scholar 

  7. Sinclair, L.V. et al. Control of amino acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat. Immunol. 14, 500–508 (2013).

    Article  CAS  Google Scholar 

  8. Pearce, E.L., Poffenberger, M.C., Chang, C.H. & Jones, R.G. Fueling immunity: insights into metabolism and lymphocyte function. Science 342, 1242454 (2013).

    Article  Google Scholar 

  9. Gabrilovich, D.I., Ostrand-Rosenberg, S. & Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12, 253–268 (2012).

    Article  CAS  Google Scholar 

  10. Norris, B.A. et al. Chronic but not acute virus infection induces sustained expansion of myeloid suppressor cell numbers that inhibit viral-specific T cell immunity. Immunity 38, 309–321 (2013).

    Article  CAS  Google Scholar 

  11. Qin, A. et al. Expansion of monocytic myeloid-derived suppressor cells dampens T cell function in HIV-1-seropositive individuals. J. Virol. 87, 1477–1490 (2013).

    Article  CAS  Google Scholar 

  12. Tacke, R.S. et al. Myeloid suppressor cells induced by hepatitis C virus suppress T-cell responses through the production of reactive oxygen species. Hepatology 55, 343–353 (2012).

    Article  CAS  Google Scholar 

  13. Vollbrecht, T. et al. Chronic progressive HIV-1 infection is associated with elevated levels of myeloid-derived suppressor cells. AIDS 26, F31–F37 (2012).

    Article  CAS  Google Scholar 

  14. Kotsakis, A. et al. Myeloid-derived suppressor cell measurements in fresh and cryopreserved blood samples. J. Immunol. Methods 381, 14–22 (2012).

    Article  CAS  Google Scholar 

  15. Brandau, S., Moses, K. & Lang, S. The kinship of neutrophils and granulocytic myeloid-derived suppressor cells in cancer: cousins, siblings or twins? Semin. Cancer Biol. 23, 171–182 (2013).

    Article  CAS  Google Scholar 

  16. Rodriguez, P.C. et al. Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res. 69, 1553–1560 (2009).

    Article  CAS  Google Scholar 

  17. Chu, C.M., Sheen, I.S., Lin, S.M. & Liaw, Y.F. Sex difference in chronic hepatitis B virus infection: studies of serum HBeAg and alanine aminotransferase levels in 10,431 asymptomatic Chinese HBsAg carriers. Clin. Infect. Dis. 16, 709–713 (1993).

    Article  CAS  Google Scholar 

  18. Cloke, T., Munder, M., Taylor, G., Muller, I. & Kropf, P. Characterization of a novel population of low-density granulocytes associated with disease severity in HIV-1 infection. PLoS ONE 7, e48939 (2012).

    Article  CAS  Google Scholar 

  19. Munder, M. et al. Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity. Blood 105, 2549–2556 (2005).

    Article  CAS  Google Scholar 

  20. Frumento, G. et al. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J. Exp. Med. 196, 459–468 (2002).

    Article  CAS  Google Scholar 

  21. Folley, S.J. & Greenbaum, A.L. Determination of the arginase activities of homogenates of liver and mammary gland: effects of pH and substrate concentration and especially of activation by divalent metal ions. Biochem. J. 43, 537–549 (1948).

    Article  CAS  Google Scholar 

  22. Ikemoto, M. et al. A useful ELISA system for human liver-type arginase, and its utility in diagnosis of liver diseases. Clin. Biochem. 34, 455–461 (2001).

    Article  CAS  Google Scholar 

  23. van de Poll, M.C. et al. Elevated plasma arginase-1 does not affect plasma arginine in patients undergoing liver resection. Clin. Sci. (Lond.) 114, 231–241 (2008).

    Article  CAS  Google Scholar 

  24. Rotondo, R. et al. Exocytosis of azurophil and arginase 1-containing granules by activated polymorphonuclear neutrophils is required to inhibit T lymphocyte proliferation. J. Leukoc. Biol. 89, 721–727 (2011).

    Article  CAS  Google Scholar 

  25. Talmadge, J.E. & Gabrilovich, D.I. History of myeloid-derived suppressor cells. Nat. Rev. Cancer 13, 739–752 (2013).

    Article  CAS  Google Scholar 

  26. Eash, K.J., Means, J.M., White, D.W. & Link, D.C. CXCR4 is a key regulator of neutrophil release from the bone marrow under basal and stress granulopoiesis conditions. Blood 113, 4711–4719 (2009).

    Article  CAS  Google Scholar 

  27. Ma, Q., Jones, D. & Springer, T.A. The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity 10, 463–471 (1999).

    Article  CAS  Google Scholar 

  28. Friedman, S.L. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol. Rev. 88, 125–172 (2008).

    Article  CAS  Google Scholar 

  29. Chou, H.S. et al. Hepatic stellate cells regulate immune response by way of induction of myeloid suppressor cells in mice. Hepatology 53, 1007–1019 (2011).

    Article  CAS  Google Scholar 

  30. Höchst, B. et al. Activated human hepatic stellate cells induce myeloid derived suppressor cells from peripheral blood monocytes in a CD44-dependent fashion. J. Hepatol. 59, 528–535 (2013).

    Article  Google Scholar 

  31. Zhao, W. et al. Hepatic stellate cells promote tumor progression by enhancement of immunosuppressive cells in an orthotopic liver tumor mouse model. Lab. Invest. 94, 182–191 (2014).

    Article  CAS  Google Scholar 

  32. Rodriguez, P.C. et al. Regulation of T cell receptor CD3zeta chain expression by L-arginine. J. Biol. Chem. 277, 21123–21129 (2002).

    Article  CAS  Google Scholar 

  33. Hayashi, K., Jutabha, P., Endou, H., Sagara, H. & Anzai, N. LAT1 is a critical transporter of essential amino acids for immune reactions in activated human T cells. J. Immunol. 191, 4080–4085 (2013).

    Article  CAS  Google Scholar 

  34. Cantor, J.M. & Ginsberg, M.H. CD98 at the crossroads of adaptive immunity and cancer. J. Cell Sci. 125, 1373–1382 (2012).

    Article  CAS  Google Scholar 

  35. Campbell, W.A. et al. TA1/LAT-1/CD98 light chain and system L activity, but not 4F2/CD98 heavy chain, respond to arginine availability in rat hepatic cells. Loss Of response in tumor cells. J. Biol. Chem. 275, 5347–5354 (2000).

    Article  CAS  Google Scholar 

  36. Schumacher, K., Maerker-Alzer, G. & Wehmer, U. A lymphocyte-inhibiting factor isolated from normal human liver. Nature 251, 655–656 (1974).

    Article  CAS  Google Scholar 

  37. Chisari, F.V. et al. Production of two distinct and independent hepatic immunoregulatory molecules by the perfused rat liver. Hepatology 5, 735–743 (1985).

    Article  CAS  Google Scholar 

  38. Sandalova, E. et al. Increased levels of arginase in patients with acute hepatitis B suppress antiviral T cells. Gastroenterology 143, 78–87 e73 (2012).

    Article  CAS  Google Scholar 

  39. Walker, L.J. et al. CD8αα expression marks terminally differentiated human CD8+ T cells expanded in chronic viral infection. Front Immunol 4, 223 (2013).

    Article  CAS  Google Scholar 

  40. Corzo, C.A. et al. HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J. Exp. Med. 207, 2439–2453 (2010).

    Article  CAS  Google Scholar 

  41. Rodriguez, P.C., Quiceno, D.G. & Ochoa, A.C. L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood 109, 1568–1573 (2007).

    Article  CAS  Google Scholar 

  42. Hara, K. et al. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J. Biol. Chem. 273, 14484–14494 (1998).

    Article  CAS  Google Scholar 

  43. Sitia, G. et al. Kupffer cells hasten resolution of liver immunopathology in mouse models of viral hepatitis. PLoS Pathog. 7, e1002061 (2011).

    Article  CAS  Google Scholar 

  44. Dunn, C. et al. Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. J. Exp. Med. 204, 667–680 (2007).

    Article  CAS  Google Scholar 

  45. Sander, L.E. et al. Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function. J. Exp. Med. 207, 1453–1464 (2010).

    Article  CAS  Google Scholar 

  46. Mieulet, V. et al. TPL-2-mediated activation of MAPK downstream of TLR4 signaling is coupled to arginine availability. Sci. Signal. 3, ra61 (2010).

    Article  Google Scholar 

  47. Sade-Feldman, M. et al. Tumor necrosis factor-alpha blocks differentiation and enhances suppressive activity of immature myeloid cells during chronic inflammation. Immunity 38, 541–554 (2013).

    Article  CAS  Google Scholar 

  48. Kong, X., Sun, R., Chen, Y., Wei, H. & Tian, Z. gammadeltaT cells drive myeloid-derived suppressor cell-mediated CD8+ T cell exhaustion in hepatitis B virus-induced immunotolerance. J. Immunol. 193, 1645–1653 (2014).

    Article  CAS  Google Scholar 

  49. Kennedy, P.T. et al. Preserved T-cell function in children and young adults with immune-tolerant chronic hepatitis B. Gastroenterology 143, 637–645 (2012).

    Article  CAS  Google Scholar 

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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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Authors and Affiliations

  1. Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK

    Laura J Pallett, Anna Schurich, Kasha P Singh, Niclas Thomas, Abhishek Das, Antony Chen & Mala K Maini

  2. Centre for Digestive Diseases, Blizard Institute, Bart's and the London School of Medicine and Dentistry, London, UK

    Upkar S Gill & Patrick T Kennedy

  3. Institute of Liver Studies, Kings College Hospital, London, UK

    Alberto Quaglia

  4. Division of Cell Signaling and Immunology, University of Dundee, Dundee, UK

    Linda V Sinclair & Doreen A Cantrell

  5. Institute of Liver and Digestive Health, University College London, London, UK

    Maria Jover-Cobos, Giuseppe Fusai & Nathan A Davies

  6. Duke-Nus Medical School, Emerging Infectious Disease Program, Singapore

    Antonio Bertoletti

  7. Singapore Institute for Clinical Sciences, Agency of Science and Technology, Singapore

    Antonio Bertoletti & Muzlifah Haniffa

  8. Institute of Cellular Medicine, Newcastle University, UK

    Muzlifah Haniffa

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Contributions

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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Correspondence to Mala K Maini.

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Competing interests

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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