Maternal-Derived Hepatitis B Virus e Antigen Alters Macrophage Function in Offspring to Drive Viral Persistence after Vertical Transmission

• Published in: Immunity (Cambridge, Mass.) Mass.), 2016-05, Vol.44 (5), p.1204-1214
• Main Authors: Tian, Yongjun, Kuo, Cheng-fu, Akbari, Omid, Ou, Jing-hsiung James
• Format: Article
• Language: English
• Subjects: Animals; Animals, Genetically Modified; Antigens; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - virology; Deoxyribonucleic acid; DNA; Families & family life; Female; Gene expression; Gene Expression Regulation; Genomes; HBV e antigen; HBV vertical transmission; Hepatitis; Hepatitis B - immunology; Hepatitis B - transmission; Hepatitis B e Antigens - immunology; Hepatitis B virus; Hepatitis B virus - physiology; Humans; Immune system; Infections; Infectious Disease Transmission, Vertical; Kupffer cells; Liver; Lymphocyte Activation; Lymphocytes; Macrophages - immunology; Macrophages - virology; Mice; Mice, Inbred C57BL; PD-1; PD-L1; Pregnancy; Prenatal Exposure Delayed Effects - immunology; Proteins; Rodents; Studies; Transgenic animals; Viral Load
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2016.04.008

In contrast to horizontal transmission of hepatitis B virus (HBV) between adults, which often leads to self-limited acute infection, vertical transmission of HBV from mother to child often leads to chronic infection. However, the mechanisms linking vertical transmission with chronic infection are not known. We developed a mouse model to study the effect of maternal HBV infection on HBV persistence in offspring and found that HBV carried by the mother impaired CD8+ T cell responses to HBV in her offspring, resulting in HBV persistence. This impairment of CD8+ T cell responses was mediated by hepatic macrophages, which were predisposed by maternal HBV e antigen (HBeAg) to support HBV persistence by upregulation of inhibitory ligand PD-L1 and altered polarization upon restimulation with HBeAg. Depletion of hepatic macrophages led to CD8+ T cell activation and HBV clearance in the offspring, raising the possibility of targeting macrophages to treat chronic HBV patients. [Display omitted] •Developed a mouse model to study effect of maternal HBV on persistence in offspring•The CTL response to HBV is impaired in the offspring of HBV-positive mothers•Depletion of macrophages in offspring restores the CTL response for HBV clearance•Maternal HBeAg enhances PD-L1 expression in macrophages of offspring to suppress CTLs Children born to mothers who carry HBV often become chronic HBV carriers. By developing a mouse model to study this vertical transmission, Ou and colleagues find that maternal HBV e antigen conditions macrophages of the offspring to suppress the CTL response to HBV, resulting in HBV persistence in the offspring.