Hepatitis B virus-induced lipid alterations contribute to natural killer T cell-dependent protective immunity

Sebastian Zeissig, Kazumoto Murata, Lindsay Sweet, Jean Publicover, Zongyi Hu, Arthur Kaser, Esther Bosse, Jahangir Iqbal, M. Mahmood Hussain, Katharina Balschun, Christoph Röcken, Alexander Arlt, Rainer Günther, Jochen Hampe, Stefan Schreiber, Jody L. Baron, D. Branch Moody, T. Jake Liang, Richard S. Blumberg

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1060-1068
Number of pages9
JournalNature Medicine
Volume18
Issue number7
DOIs
StatePublished - Jul 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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  • Cite this

    Zeissig, S., Murata, K., Sweet, L., Publicover, J., Hu, Z., Kaser, A., Bosse, E., Iqbal, J., Hussain, M. M., Balschun, K., Röcken, C., Arlt, A., Günther, R., Hampe, J., Schreiber, S., Baron, J. L., Branch Moody, D., Jake Liang, T., & Blumberg, R. S. (2012). Hepatitis B virus-induced lipid alterations contribute to natural killer T cell-dependent protective immunity. Nature Medicine, 18(7), 1060-1068. https://doi.org/10.1038/nm.2811