Mapping self-associating chromatin hubs identifies Id proteins as key determinants of exhausted CD8⁺ T cell fate

Within days of exposure to chronic viral infections, activated CD8⁺ T cells differentiate into Tcf1^-Slamf6^loTim3^hi exhaustion-prone effector T (T_{EX_EFF}) cells or self-renewing Tcf1⁺Slamf6^hiTim3^lo precursor exhausted T (T_PEX) cells. Here we showed that early CD8⁺ T_EX cell fates were imprinted by forming subset-specific, self-associating chromatin hubs. Chromatin hub assembly coincided with effector or stemness gene induction and identified the transcription cofactors Id2 and Id3 as key regulators that promoted CD8⁺ T_{EX_EFF} and CD8⁺ T_PEX cell fates, respectively. Id2 drove CD8⁺ T_{EX_EFF} cell specification by activating effector genes, while suppressing genes involved in exhaustion and stemness. In contrast, Id3-repressed effector genes but upregulated IL-7Rα and AhR, thereby maintaining the CD8⁺ T_PEX cell pool. Mechanistically, Id2 and Id3 exhibited a distinct impact on the chromatin accessibility landscape in early CD8⁺ T_EX cells by engaging Runx3 and Tcf1 transcription factors along with E proteins. These findings indicated that reshaping chromatin architecture represents a critical means for specifying CD8⁺ T_EX cell fates and ensuring lineage stability.