Gene regulatory network determinants of rapid recall in human memory CD4+ T cells

Rapid recall is the hallmark of memory T cells. While naive T cells require days to mount an effector response to a new threat, antigen-experienced memory T cells can produce cytokines within hours of the repeat encounter. The establishment of memory and control of rapid recall across lifespan is poorly understood, yet the mechanisms are fundamental to pathogen defense and immunological diseases. Epigenetic poising was proposed as a likely mechanism. Indeed, compared to naive, memory cells exhibit enhanced chromatin accessibility proximal to rapid recall genes, but the transcription factors (TFs) that establish, maintain and utilize these putative regulatory elements are unknown. Here, we leverage single-nuclei (sn)multiome-seq (simultaneous snRNA-seq and snATAC-seq) to (1) characterize the dynamic activation responses of naive and memory CD4+ T cell subsets and (2) reconstruct the underlying gene regulatory networks, at genome scale. Our analysis uncovered thousands of genes and putative regulatory elements with rapid-recall dynamics, shared and unique across the memory populations. A core of memory-associated TFs (MAF, PRDM1, RUNX2, RBPJ and KLF6) is predicted to orchestrate rapid recall and maintain accessible chromatin at rapid-recall gene enhancers in resting memory cells. 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 gene regulatory mechanisms that might mediate genetic risk to autoimmune and inflammatory diseases.