Memory T cell rapid recall is driven by memory-specific AP-1 recruitment determined by epigenome and co-factor interactions

ABSTRACT CD4 T cell memory is essential for long-lasting protective immunity to repeat infections. Unlike naïve T cells, memory cells possess rapid recall ability to quickly produce effector molecules in response to antigen re-exposure. This ability was shown to be associated with epigenetic gene poising. Here, we examine how the activation-inducible transcription factors, AP□1 and NF□κB, regulate rapid recall gene expression. We found that AP-1 is required for their induction and that the enhanced induction of rapid recall genes in memory cells is associated with memory-specific binding of AP□1. Memory-specific AP□1 binding, in turn, is enabled by enhanced chromatin accessibility and reduced DNA methylation at regulatory elements. As the AP-1 DNA-binding motif itself does not contain methylatable CpGs, methylation likely affects the binding of AP-1 co-factors, such as ETS proteins, or accessibility of the region in general. Finally, both common and memory-specific AP□1/NF□κB binding sites show strong overlap with autoimmune and inflammatory disease risk variants, highlighting the clinical relevance of memory T cell epigenetic regulation. Competing Interest Statement A.B. is a co-founder of and M.K. and A.B. are employed part-time by Datirium, LLC. Datirium created the Scientific Data Analysis platform, https://scidap.com, used to analyze the next-generation sequencing data in this study. A.B. is an unpaid member of the Scientific Advisory Board of Lysosomal & Rare Disorders Research & Treatment Center (LDRTC), LLC.