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.
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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.
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Zeissig, S., Murata, K., Sweet, L. et al. Hepatitis B virus–induced lipid alterations contribute to natural killer T cell–dependent protective immunity. Nat Med 18, 1060–1068 (2012). https://doi.org/10.1038/nm.2811
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DOI: https://doi.org/10.1038/nm.2811
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