Faculty Opinions recommendation of Anti-mycobacterial activity correlates with altered DNA methylation pattern in immune cells from BCG-vaccinated subjects.

The reason for the largely variable protective effect against TB of the vaccine Bacille Calmette-Guerin (BCG) is not understood.In this study, we investigated whether epigenetic mechanisms are involved in the response of immune cells to the BCG vaccine.We isolated peripheral blood mononuclear cells (PBMCs) from BCG-vaccinated subjects and performed global DNA methylation analysis in combination with functional assays representative of innate immunity against Mycobacterium tuberculosis infection.Enhanced containment of replication was observed in monocyte-derived macrophages from a subgroup of BCG-vaccinated individuals (identified as 'responders').A stable and robust differential DNA methylation pattern in response to BCG could be observed in PBMCs isolated from the responders but not from the non-responders.Gene ontology analysis revealed that promoters with altered DNA methylation pattern were strongly enriched among genes belonging to immune pathways in responders, however no enrichments could be observed in the non-responders.Our findings suggest that BCG-induced epigenetic reprogramming of immune cell function can enhance anti-mycobacterial immunity in macrophages.Understanding why BCG induces this response in responders but not in nonresponders could provide clues to improvement of TB vaccine efficacy.Tuberculosis (TB) is one of the leading causes of death from infectious disease worldwide.The only available TB vaccine is Bacille Calmette Guérin (BCG), which has low efficacy against adult pulmonary TB.Since the pulmonary manifestation of TB is the major source of transmission, an effective prevention strategy against pulmonary TB is urgently needed.New vaccine candidates are based on the addition of Mycobacterium tuberculosis (Mtb) antigens to the BCG regimen, however none has yet provided better protection than BCG 1 .Effective vaccine development is facilitated by the use of immunological correlates, which may predict the outcome of vaccination.For TB vaccine research, the general strategy is to measure mycobacteria-specific T cell responses, however, earlier studies have failed to prove such a correlation 2 , suggesting that other protective mechanisms may be at play.Evidence is accumulating that during lifetime, the human immune system is gradually epigenetically reprogrammed.Both DNA methylation changes (e.g.demethylation of transcription start sites enhances transcriptional activity 3 ) and histone modifications (e.g.histone acetylation/methylation increases or decreases the accessibility of DNA to transcription factors 4 ) contribute to this phenomenon.Post-translational histone modifications in immune cells have been shown to result in an enhanced response to microbial stimuli 5,6 .Furthermore, altered DNA methylation has been demonstrated in a subset of natural killer (NK) cells isolated from cytomegalovirus-infected humans 7 .However, nothing is known about genome-wide DNA methylation changes in response to vaccination.