Hepatitis B virus-induced lipid alterations contribute to natural killer T cell-dependent protective immunity.
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.
Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Sebastian
S
Zeissig
Kazumoto
K
Murata
Lindsay
L
Sweet
Jean
J
Publicover
Zongyi
Z
Hu
Arthur
A
Kaser
Esther
E
Bosse
Jahangir
J
Iqbal
M Mahmood
MM
Hussain
Katharina
K
Balschun
Christoph
C
Röcken
Alexander
A
Arlt
Rainer
R
Günther
Jochen
J
Hampe
Stefan
S
Schreiber
Jody L
JL
Baron
D Branch
DB
Moody
T Jake
TJ
Liang
Richard S
RS
Blumberg
D056704:Adaptive Immunity / Q000276:immunology; D000256:Adenoviridae; D000818:Animals; D055610:Antigens, CD1d / Q000378:metabolism; D015415:Biomarkers; D002352:Carrier Proteins / Q000378:metabolism; D018920:Coculture Techniques; D006514:Hepatitis B Surface Antigens / Q000276:immunology; D006515:Hepatitis B virus / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000517:prevention & control* / Q000821:virology; D022781:Hepatocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D006801:Humans; D007109:Immunity / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D050356:Lipid Metabolism / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008246:Lysophospholipids / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D055611:Natural Killer T-Cells / Q000276:immunology*; D054497:Phospholipases A2, Secretory / Q000378:metabolism
D055610:Antigens, CD1d; D015415:Biomarkers; D002352:Carrier Proteins; D006514:Hepatitis B Surface Antigens; D008246:Lysophospholipids; C008301:lysophosphatidylethanolamine; C106092:microsomal triglyceride transfer protein; D007371:Interferon-gamma; D054497:Phospholipases A2, Secretory