Abstract

In most adult humans, hepatitis B is a self-limiting disease leading to life-long protective immunity, which is the consequence of a robust adaptive immune response occurring weeks after hepatitis B virus (HBV) infection. Notably, HBV-specific T cells can be detected shortly after infection, but the mechanisms underlying this early immune priming and its consequences for subsequent control of viral replication are poorly understood. Using primary human and mouse hepatocytes and mouse models of transgenic and adenoviral HBV expression, we show that HBV-expressing hepatocytes produce endoplasmic reticulum (ER)-associated endogenous antigenic lipids including lysophospholipids that are generated by HBV-induced secretory phospholipases and that lead to activation of natural killer T (NKT) cells. The absence of NKT cells or CD1d or a defect in ER-associated transfer of lipids onto CD1d results in diminished HBV-specific T and B cell responses and delayed viral control in mice. NKT cells may therefore contribute to control of HBV infection through sensing of HBV-induced modified self-lipids.

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Acknowledgements

This work was supported by US National Institutes of Health (NIH) grants DK51362, DK44319, DK53056, DK88199, the Harvard Digestive Diseases Center DK034854 (to R.S.B.); the Deutsche Forschungsgemeinschaft (Ze 814/1-1, Ze 814/4-1), a Marie Curie International Reintegration Grant within the 7th European Community Framework Programme (256363) and the Crohn's and Colitis Foundation of America (to S.Z.); the Crohn's and Colitis Foundation of America, Austrian Science Fund, and Max Kade Foundation (to A.K.); NIH AR048632, AI049313 and the Burroughs Wellcome Fund for Translational Research (to D.B.M.); DK46900 (to M.M.H.); the NIH Intramural Research Program (K.M., Z.H. and T.J.L.); NIH grants AI068090, DK026743 and the Burroughs Wellcome Fund (to J.L.B.); and the A.P. Gianinni Foundation (to J.P.). We thank D.E. Cohen, E. Scapa and S.K. Dougan for insightful discussions.

Author information

Author notes

    • Arthur Kaser

    Present address: Division of Gastroenterology and Hepatology, Addenbrooke's Hospital, School of Clinical Medicine, University of Cambridge, Cambridge, UK.

    • T Jake Liang
    •  & Richard S Blumberg

    These authors contributed equally to this work.

Affiliations

  1. Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Sebastian Zeissig
    • , Arthur Kaser
    •  & Richard S Blumberg
  2. Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany.

    • Sebastian Zeissig
    • , Esther Bosse
    • , Alexander Arlt
    • , Rainer Günther
    • , Jochen Hampe
    •  & Stefan Schreiber
  3. Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, USA.

    • Kazumoto Murata
    • , Zongyi Hu
    •  & T Jake Liang
  4. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts USA.

    • Lindsay Sweet
    •  & D Branch Moody
  5. Department of Medicine, Liver Center, University of California–San Francisco, San Francisco, California, USA.

    • Jean Publicover
    •  & Jody L Baron
  6. Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York, USA.

    • Jahangir Iqbal
    •  & M Mahmood Hussain
  7. Department of Pediatrics, State University of New York Downstate Medical Center, Brooklyn, New York, USA.

    • M Mahmood Hussain
  8. Department of Pathology, University Medical Center Schleswig-Holstein, Campus Kiel, Christian-Albrechts-University, Kiel, Germany.

    • Katharina Balschun
    •  & Christoph Röcken

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Contributions

S.Z. designed, performed and analyzed experiments and prepared the manuscript with R.S.B. and T.J.L.; K.M. and Z.H. generated adenoviruses and adenoviral mutants and contributed to Ad-HBV studies; L.S. and D.B.M. designed, performed and analyzed LC-MS experiments together with S.Z.; J.P. and J.L.B. designed, performed and analyzed studies with HBV-Env mice; A.K. generated H-Mttp−/− mice and contributed to their characterization; K.B. and C.R. performed histopathological analyses; M.M.H. and J.I. obtained purified MTP; E.B. performed PLA2 inhibitor and siRNA studies; R.G. obtained primary HBV isolates; A.A. and J.H. contributed to human hepatocyte studies; S.S. contributed to supervision of the studies; T.J.L. and R.S.B. supervised the studies.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to T Jake Liang or Richard S Blumberg.

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DOI

https://doi.org/10.1038/nm.2811

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