An experimentally-refined dynamic gene regulatory network model of T-cell memory with Artem Barski, PhD.
Long-lived memory T cells are critical for protective immunity. Upon secondary exposure to pathogen, memory T cells mount an immediate defense, rapidly producing lineage-characteristic cytokines. In contrast, naïve T cells require days to produce cytokines after initial exposure. While this “rapid recall ability” of memory T cells is critical for pathogen defense and is the basis for vaccination, it also underlies allergy, asthma and anti-cancer immunity. Unfortunately, little is known about the mechanism(s) by which memory T cells are endowed with the ability to rapidly produce cytokines. Notably, such knowledge could be exploited to promote protective (e.g., vaccines, anti-cancer immunity) or to reduce pathologic (e.g., asthma, allergy, and autoimmunity) responses.
The aim of this collaboration is to create an experimentally-validated, genome-scale model of memory immune response. Using single-cell genomics, we are characterizing the gene expression and chromatin dynamics of T cell activation in naïve and memory cells and building mathematical models that integrate these data (along with relevant existing genomics resources) into a dynamic gene regulatory network (GRN). Our GRN model will predict the molecular drivers (transcription factors) and regulatory elements that orchestrate rapid recall – hypotheses we will test with dynamic TF perturbation and occupancy measurements.
Although T-cell activation in naïve and memory cells similarly promotes nuclear translocation of inducible TFs, our data lead us to hypothesize that (1) chromatin remodeling upon initial pathogen exposure alters the occupancy of inducible TFs in memory T cells, and (2) this is the basis of rapid recall.
We also aim to identify the mechanisms by which memory T cells maintain the epigenome conducive for rapid recall – over the human lifespan. We hypothesize that constitutive TFs maintain the epigenome poised for rapid recall. This study will help uncover basic mechanisms of T cell memory and identify potential targets for manipulating immunologic memory responses. Because rapid recall is the basis for vaccination and central to allergy, asthma, and cancer immunity, this study will have a broad impact on human health.