Low levels of OX40 ligand (OX40L) in hepatic antigen-presenting cells (APCs) underlie the inability of infants to mount an effective adaptive immune response to hepatitis B, according to a new study.
The majority of individuals with chronic hepatitis B contract the virus during childhood, in large part due to the poor immune response initiated to the virus in the young liver. By contrast, a robust adaptive immune response to HBV infection is typically mounted in adults, leading to spontaneous viral clearance in the majority of cases.
In previous work, Jody Baron and colleagues developed a model of HBV infection — the HBVtgRag−/− mouse — that combines transgenic hepatic expression of HBV antigens and intact virus with Rag1 deficiency (leading to a lack of mature B and T cells, including cells tolerant to HBV). “To mimic the point of viral infection, these mice receive an adoptive transfer of an HBV-naïve immune system,” explains Baron. Results from this model suggested that priming of intrahepatic T follicular helper (TFH) cells, which produce IL-21, is critical for promoting effective adult CD8+ T cell and B cell responses to HBV. “For this reason, we embarked on studies to identify molecules on hepatic APCs that are expressed in an age-dependent manner, which might contribute to effective immune priming to HBV,” says author Jean Publicover.
As an initial step, Baron and colleagues assessed the expression of costimulatory molecules that are important for the induction of T cell responses. Expression of OX40L in liver-resident and monocyte-derived hepatic macrophages was markedly increased in adult mice compared with young mice, despite no age-related differences in the absolute numbers of hepatic APCs. To assess the functional significance of OX40L and its receptor OX40 in the HBV immune response, splenocytes from Ox40−/− or wild-type adult mice were transferred into HBVtgRag−/− mice. Notably, intact OX40 was required for the development of hepatitis, clearance of hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (HBsAb) seroconversion, as well as generation of HBV-specific CD4+ and CD8+ T cell responses and the induction of TFH cell-derived IL-21 expression.
To test the hypothesis that OX40 signalling in HBVtgRag−/− mice could improve HBV immune responses, Baron and colleagues administered wild-type splenocytes alongside an OX40 agonist or a control agent. OX40 agonism increased CD4+ T cell and TFH cell numbers and improved HBsAg clearance. Interestingly, clearance of HBsAg occurred without HBsAb production, suggesting that a strong T cell response can control HBV in the absence of detectable levels of HBsAb.
To confirm the clinical relevance of these findings, the researchers assessed OX40L expression in human liver biopsy tissue and OX40 expression in peripheral blood from patients acutely and chronically infected with HBV. Supporting the findings in mice, infant liver tissue had lower levels of OX40L mRNA than adult tissue, and increased expression of OX40 on peripheral CD4+ T cells was associated with effective viral clearance.
“We are working on ways to target the OX40–OX40L pathway in chronic HBV, and testing its therapeutic potential both alone and in conjunction with modulation of other immune pathways” concludes Baron. “We believe such approaches will provide novel and much needed therapeutic interventions for this globally important disease.”