Reporting in Cell, Bali Pulendran and colleagues describe the epigenetic and transcriptional changes, occurring at a single-cell level, in humans in response to influenza virus vaccination. They showed that the trivalent inactivated seasonal influenza vaccine (TIV) induced global changes to the chromatin state — including acetylation, methylation and phosphorylation — in multiple immune cell subsets. The changes persisted for up to 6 months and were most pronounced in myeloid cells. Notably, in classical monocytes and myeloid dendritic cells, acetylation of multiple histones was repressed 30 days after vaccination and returned to baseline levels at day 180. Transcriptomics revealed this repression coincided with downregulation of histone acetyltransferases and the arginine deiminase PADI4 and upregulation of histone deacetylases. Moreover, hypoacetylation was associated with diminished cytokine responses following Toll-like receptor (TLR) stimulation of peripheral blood mononuclear cells at day 30 after vaccination.

Analysis of chromatin accessibility using ATAC-seq of purified immune cell subsets post vaccination revealed thousands of regions of reduced chromatin accessibility in myeloid cells, including genes for cytokines, chemokines, pattern recognition receptors and adhesion molecules, indicating reduced gene activity. A subcluster of monocytes showed reduced chromatin accessibility at regions targeted by AP-1 family transcription factors, which are responsible for production of pro-inflammatory cytokines and TLR signalling molecules.

The finding of immune refractoriness following TIV is at odds with previous studies describing enhanced and persistent innate responses — termed trained immunity — following live attenuated BCG vaccination, leading the authors to hypothesize that lack of adjuvant signals in TIV may explain the induction of a form of trained tolerance. Addition of the adjuvant AS03 to H5N1 pandemic influenza vaccine led to a similar repressive state — hypoacetylation of histones, reduced AP-1 accessibility and diminished cytokine and chemokine production — as observed with TIV. However, the adjuvanted vaccine also induced increased chromatin accessibility for interferon-response factors and STAT family members, leading to increased expression of antiviral genes such as interferons. This was associated with enhanced resistance to unrelated Zika and dengue viruses in vitro.

So, the authors suggest that the coexistence of immune refractoriness and antiviral vigilance — within the same cell — allows for the avoidance of immunopathology while maintaining viral immunity.