Flexible and scalable control of T cell memory by a reversible epigenetic switch

Abstract

The immune system encodes information about the severity of a pathogenic threat in the quantity and type of memory cell populations formed in response. This encoding emerges from the decisions of lymphocytes to maintain or lose self-renewal and memory potential during a challenge. By tracking CD8 T cells at the single-cell and clonal level using time-resolved transcriptomics and quantitative imaging, we identify a flexible memory strategy, whereby T cells initially choose whether to maintain or lose memory potential early after antigen recognition, but following pathogen clearance may regain memory potential if initially lost. This flexibility is implemented by a cis-epigenetic switch silencing the memory regulator TCF1 in a stochastic, reversible manner in response to stimulatory inputs. Mathematical modeling shows how this strategy allows memory cell numbers to scale robustly with pathogen virulence and immune response magnitudes. Thus, flexibility in cellular decision making ensures optimal 39 immune responses against diverse threats.

The association between lymphocyte-to-monocyte ratio and all-cause mortality in obese hypertensive patients with diabetes and without diabetes: results from the cohort study of NHANES 2001–2018

“…Since LMR consists of lymphocyte and monocyte counts, it has the advantage of being relatively inexpensive and can be obtained routinely. A low lymphocyte count indicates a persistent, relatively deficient immune state, and a high monocyte count indicates a nonspecific or systemic inflammatory state (19)(20)(21)(22). As a composite parameter reflecting two opposing immune and inflammatory pathways, LMR is more predictive than lymphocyte or monocyte alone.…”

A timed epigenetic switch balances T and ILC lineage proportions in the thymus

“…The activation timing of genes is often assumed to depend solely on the activity of upstream trans -factors. However, across a range of systems, epigenetic switches, acting in cis at individual gene loci, can delay the activation of lineage-specifying genes after initial exposure to developmental signals (Abadie et al, 2023; Berry et al, 2017; Bintu et al, 2016; Hathaway et al, 2012; Ng et al, 2018), sometimes by multiple days and cell generations. These time delays in epigenetic switching vary both between single cells and between individual gene loci in the same cell due to the stochastic nature of chromatin regulation (Bintu et al, 2016; Dodd et al, 2007; Festenstein et al, 1996; Owen et al, 2023) However, despite this stochasticity, probabilistic time constants of switching are precisely modulated at multiple levels, including by cytokine signaling, transcription factors (TFs), and associated cis -regulatory elements and chromatin-modifying enzymes (Chu et al, 2021; Deschamps and Duboule, 2017; Fabre et al, 2015; Kissiov et al, 2022; Pease et al, 2021).…”