32 / 2026-03-18 19:41:18

3D genome remodeling during CD8⁺ T cell exhaustion

CD8+ T cells,3D genome,Transcription factors,Exhaustion

CD8⁺ T cells are rendered exhausted in cancer, accompanied by extensive changes in epigenome. However, whether and how higher-order chromatin organization is involved in exhausted CD8⁺ T cell differentiation is unclear. Here, we showed extensive changes in the three-dimensional genome during T cell exhaustion, associated with changes in gene transcription. Moreover, we identified interferon regulatory factor 8 (IRF8) as an essential transcription factor in re-organization of the spatial proximity between enhancers and promoters of genes associated with exhausted T cell differentiation. Irf8 deficiency inhibited the differentiation of exhausted CD8⁺ T cells and their anti-tumor function. Mechanistically, IRF8 bound to genes associated with exhausted T cell differentiation and promoted the formation of intra-TAD chromosomal loops. At the loop anchor regions, IRF8 recruited CTCF to form active chromosomal structure to regulate gene transcription. These results thus identify a critical role of IRF8-dependent chromatin topology during exhausted CD8⁺ T cell differentiation.