An OX40/OX40L interaction directs successful immunity to hepatitis B virus

作者：Publicover Jean; Gaggar Anuj; Jespersen Jillian M; Halac Ugur; Johnson Audra J; Goodsell Amanda; Avanesyan Lia; Nishimura Stephen L; Holdorf Meghan; Mansfield Keith G; Judge Joyce Bousquet; Koshti Arya; Croft Michael; Wakil Adil E; Rosenthal Philip; Pai Eric; Cooper Stewart; Baron Jody L^*

来源：Science Translational Medicine, 2018, 10(433): eaah5766.

DOI：10.1126/scitranslmed.aah5766

Depending on age of acquisition, hepatitis B virus (HBV) can induce a cell-mediated immune response that results in either cure or progressive liver injury. In adult-acquired infection, HBV antigens are usually cleared, whereas in infancy-acquired infection, they persist. Individuals infected during infancy therefore represent the majority of patients chronically infected with HBV (CHB). A therapy that can promote viral antigen clearance in most CHB patients has not been developed and would represent a major health care advance and cost mitigator. Using an age-dependent mouse model of HBV clearance and persistence in conjunction with human blood and liver tissue, we studied mechanisms of viral clearance to identify new therapeutic targets. We demonstrate that age-dependent expression of the costimulatory molecule OX40 ligand (OX40L) by hepatic innate immune cells is pivotal in determining HBV immunity, and that treatment with OX40 agonists leads to improved HBV antigen clearance in young mice, as well as increased strength of T cell responses in young mice and adult mice that were exposed to HBV when they were young and developed a CHB serological profile. Similarly, in humans, we show that hepatic OX40L transcript expression is age-dependent and that increased OX40 expression on peripheral CD4(+) T cells in adults is associated with HBV clearance. These findings provide new mechanistic understanding of the immune pathways and cells necessary for HBV immunity and identify potential therapeutic targets for resolving CHB.

• 出版日期2018-3-21