Antigen exposure reshapes chromatin architecture in central memory CD8⁺ T cells and imprints enhanced recall capacity

CD62L⁺ central memory CD8⁺ T (T_CM) cells provide enhanced protection than naive cells; however, the underlying mechanism, especially the contribution of higher-order genomic organization, remains unclear. Systematic Hi-C analyses reveal that antigen-experienced CD8⁺ T cells undergo extensive rewiring of chromatin interactions (ChrInt), with T_CM cells harboring specific interaction hubs compared with naive CD8⁺ T cells, as observed at cytotoxic effector genes such as Ifng and Tbx21. T_CM cells also acquire de novo CTCF (CCCTC-binding factor) binding sites, which are not only strongly associated with T_CM-specific hubs but also linked to increased activities of local gene promoters and enhancers. Specific ablation of CTCF in T_CM cells impairs rapid induction of genes in cytotoxic program, energy supplies, transcription, and translation by recall stimulation. Therefore, acquisition of CTCF binding and ChrInt hubs by T_CM cells serves as a chromatin architectural basis for their transcriptomic dynamics in primary response and for imprinting the code of "recall readiness" against secondary challenge.