Background
IgE-mediated food allergies have been linked to suboptimal T cell responses in infancy, which have been associated with epigenetic differences. A recent study documented similar attenuated nCD4T cell responses in food-allergic (FA) adolescents, but these are yet to be linked to epigenetic changes.
Methods
We generated genome-wide DNA methylation data from nCD4 T cells following 72h culture with media alone (quiescent) or with anti-CD3/anti-CD28 beads (activated) in a cohort of adolescents with peanut/multi-food allergy (n=29), alongside age-matched non-allergic controls (n=18). Additionally, we assessed gene expression of these cells following activation, and compared this with previously published cytokine data and open chromatin signatures.
Results
Our data reveals that FA adolescents show altered methylation profiles following activation at genes linked to the NOD-like receptor signalling pathway, a key regulator of viral responses. We also show that FA adolescents exhibit unique epigenetic signatures at both quiescent and activated conditions, with differential methylation observed at key Th1/Th2 differentiation genes (RUNX3, RXRA, NFKB1A, IL4R) and a differentially methylated region found at the TNFRSF6B promoter, a gene previously linked to Th1 proliferation and implicated in diseases such as rheumatoid arthritis, psoriasis and systemic lupus erythematosus. Moreover, combined analysis of DNA methylation, transcriptomic data, cytokine output and open chromatin signatures identifies an attenuated interferon response in nCD4T cells from FA individuals following activation. This included decreased expression of IFN-g across gene expression and cytokine profiles, as well as a DMR showing increased methylation in FA at an interferon stimulated gene, BST2 .
Conclusion
We demonstrate that attenuated responses in nCD4T cells from peanut and multi-food allergic are associated with epigenetic changes, with peanut and multi-food allergic adolescents showing extensive disruption of interferon responses, suggesting dysregulation of immune pathways contributing to this persistent and severe FA phenotype.