The transcriptional cofactor Tle3 reciprocally controls effector and central memory CD8⁺ T cell fates

Antigen-experienced CD8⁺ T cells form effector and central memory T cells (T_EM and T_CM cells, respectively); however, the mechanism(s) controlling their lineage plasticity remains incompletely understood. Here we show that the transcription cofactor Tle3 critically regulates T_EM and T_CM cell fates and lineage stability through dynamic redistribution in antigen-responding CD8⁺ T cell genome. Genetic ablation of Tle3 promoted CD8⁺ T_CM cell formation at the expense of CD8⁺ T_EM cells. Lineage tracing showed that Tle3-deficient CD8⁺ T_EM cells underwent accelerated conversion into CD8⁺ T_CM cells while retaining robust recall capacity. Tle3 acted as a coactivator for Tbet to increase chromatin opening at CD8⁺ T_EM cell-characteristic sites and to activate CD8⁺ T_EM cell signature gene transcription, while engaging Runx3 and Tcf1 to limit CD8⁺ T_CM cell-characteristic molecular features. Thus, Tle3 integrated functions of multiple transcription factors to guard lineage fidelity of CD8⁺ T_EM cells, and manipulation of Tle3 activity could favor CD8⁺ T_CM cell production.