Gene regulatory network determinants of rapid recall in human memory T cells 3929

Abstract Description Rapid recall is the hallmark of memory T cells. While naïve T cells require days to mount an effector response to new antigen, antigen-experienced memory T cells produce cytokine within hours of second encounter to antigen. The encoding of memory and control of rapid recall across lifespan is poorly understood, yet the mechanisms are fundamental to pathogen defense and inflammatory diseases. Chromatin poising is a likely mechanism. Proximal to rapid recall genes, putative regulatory elements exhibit differential chromatin states between memory versus naïve T cells, but the transcription factors (TFs) that establish and potentially maintain these states are unknown. Here, we leverage single-nuclei gene expression (snRNA-seq) linked to chromatin accessibility (snATAC-seq) to characterize the dynamic responses of naïve versus memory CD4+ T cells to T-cell receptor (TCR) stimulation. From these data, we infer gene regulatory networks, enabling identification of transcripts, TFs and regulatory elements encoding memory maintenance and memory formation. Our sc-resolved, genome-scale analyses expand the definition of rapid recall genes and their putative regulatory elements, shared and unique across T effector and central memory populations. We integrate GWAS to link our T cell populations and their dynamic chromatin landscapes to human phenotypes, nominating CD4+ T cell populations, rapid recall responses and accessible chromatin regions that might mediate genetic disease risks. Funding Sources R01AI153442 Topic Categories Computational and Systems Immunology (COMP)