%0 Journal Article
%T Reversible, tunable epigenetic silencing of TCF1 generates flexibility in the T cell memory decision.
%A Abadie K
%A Clark EC
%A Valanparambil RM
%A Ukogu O
%A Yang W
%A Daza RM
%A Ng KKH
%A Fathima J
%A Wang AL
%A Lee J
%A Nasti TH
%A Bhandoola A
%A Nourmohammad A
%A Ahmed R
%A Shendure J
%A Cao J
%A Kueh HY
%J Immunity
%V 57
%N 2
%D 2024 Feb 13
%M 38301652
%F 43.474
%R 10.1016/j.immuni.2023.12.006
%X The immune system encodes information about the severity of a pathogenic threat in the quantity and type of memory cells it forms. This encoding emerges from lymphocyte decisions to maintain or lose self-renewal and memory potential during a challenge. By tracking CD8+ T cells at the single-cell and clonal lineage level using time-resolved transcriptomics, quantitative live imaging, and an acute infection model, we find that T cells will maintain or lose memory potential early after antigen recognition. However, following pathogen clearance, T cells may regain memory potential if initially lost. Mechanistically, this flexibility is implemented by a stochastic cis-epigenetic switch that tunably and reversibly silences the memory regulator, TCF1, in response to stimulation. Mathematical modeling shows how this flexibility allows memory T cell numbers to scale robustly with pathogen virulence and immune response magnitudes. We propose that flexibility and stochasticity in cellular decisions ensure optimal immune responses against diverse threats.