Role of transcription factor RUNX1 in the maintenance of T helper cell epigenome and rapid recall response

Abstract Memory T cells exhibit an accelerated response after a second encounter with the same antigen. In our previous studies, we showed that the ability to produce effector molecules within minutes of the secondary exposure to antigen (“rapid recall response”) is associated with the epigenetic state of the rapid recall genes. This memory epigenome is established during the primary T cell encounter with its cognate antigen. To maintain a “rapid recall response” even when antigen is eliminated, resting memory T cells would have to maintain open chromatin signature for years despite episodic homeostatic T cell proliferation. However, the mechanisms underlying the long-term maintenance of this epigenetic pattern remains unclear. Here, we used 10X Multiome (scRNA-seq and scATAC-seq obtained from the same cells) analysis to show that the association between the chromatin state of memory cells and their cytokine expression upon activation is Th lineage specific. Bioinformatic analysis showed that open chromatin specific for memory but not naïve CD4 T cells is enriched with motifs of constitutively expressed transcription factors RUNX, SP1, and ETS. Our preliminary Cut&Tag data in total human resting CD4 T cells demonstrates that RUNX1 binds DNA close to T helper cytokines genes (IL3, IL4, IL9, IL10, IL13, IFNG) at “memory-specific” ATAC-seq regions, suggesting the role of RUNX1 in maintaining this “rapid recall” epigenome. Together with the dynamic model of transcriptome and epigenome rearrangements this data could help us to understand how memory T cells establish a platform that enables and maintains their unique ability to respond more rapidly to subsequent encounters with antigen. Supported by R01AI153442-01A1 from NIAID, NIH