Multidimensional epigenomic priming of inflammatory genes enables rapid recall in human memory T cells

During T cell responses, a fraction of activated cells adopts a memory phenotype and returns to quiescence. These long-lived memory T cells retain an irreversible molecular imprint that enables them to mount a secondary recall response to the same antigen that is faster and greater in magnitude than the primary response of a naive cell. Memory T cells provide long-lasting immunological protection, forming the foundation for vaccination strategies and representing prime targets for immunotherapies to treat diseases characterized by dysfunctional memory T cells - including cancer and chronic inflammation. The molecular circuitry that endows memory T cells with their rapid recall ability remains incompletely understood. Here, we applied a multi-layered 1D-3D epigenomics approach to systematically dissect the molecular program driving rapid recall in primary human Th2 cells. Overall design: Various omics datasets were generated from purified human naive and memory CD4+ T cells (n=3 donors) prior to and after T cell receptor stimulation. Findings were validated using flowcytometry, inhibitor studies and CRISPR-Cas9 genome editing in primary human CD4+T cells.