The response to influenza vaccination is associated with DNA methylation-driven regulation of T cell innate antiviral pathways

TL;DR

This study shows that DNA methylation patterns in T cells are linked to how well people respond to the influenza vaccine.

Contribution

The study identifies 179 DNA methylation sites that predict vaccine response and links them to RIG-I signaling and BRD4 transcription factors.

Findings

179 methylation sites predict seroprotection against influenza.

These sites are enriched in genes related to RIG-I signaling and innate immunity.

BRD4 binding sites are associated with T cell memory and vaccine response.

Abstract

The effect of vaccination on the epigenome remains poorly characterized. In previous research, we identified an association between seroprotection against influenza and DNA methylation at sites associated with the RIG-1 signaling pathway, which recognizes viral double-stranded RNA and leads to a type I interferon response. However, these studies did not fully account for confounding factors including age, gender, and BMI, along with changes in cell type composition.

Here, we studied the influenza vaccine response in a longitudinal cohort vaccinated over two consecutive years (2019–2020 and 2020–2021), using peripheral blood mononuclear cells and a targeted DNA methylation approach. To address the effects of multiple factors on the epigenome, we designed a multivariate multiple regression model that included seroprotection levels as quantified by the hemagglutination-inhibition (HAI) assay test.

Our findings indicate that 179 methylation sites can be combined as potential signatures to predict seroprotection. These sites were not only enriched for genes involved in the regulation of the RIG-I signaling pathway, as found previously, but also enriched for other genes associated with innate immunity to viruses and the transcription factor binding sites of BRD4, which is known to impact T cell memory. We propose a model to suggest that the RIG-I pathway and BRD4 could potentially be modulated to improve immunization strategies.

Figures