Analysis of 3-dimensional genome of exhausted CD8+ T cells reveals a critical role of IRF8 in their terminal differentiation in cancer [ChIP]

Exhausted CD8+ T cell differentiation is 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 exhausted CD8+ T cell differentiation, associated with changes in gene transcription. Moreover, we identified Interferon regulatory factor 8 (IRF8) as an essential transcription factor in re-organization of spatial chromosomal interactions. Irf8 deficiency inhibits the development of terminal exhausted CD8+ T cells and promotes tumor growth. Mechanistically, IRF8 bound to genes associated with exhausted CD8+ T cells differentiation and promoted the formation of chromosomal loops. At the loop anchor regions, IRF8 recruited CTCF to form active chromosomal structure to regulated exhaustion-associated genes. These results thus identify a critical role of IRF8-dependent chromatin topology in gene transcription during exhausted CD8+ T cell differentiation. Overall design: Chromatin immunoprecipitation DNA-sequencing (ChlP-seg) for IRF8 and CTCF of Irf8fl/fl vs Irf8-/- CD8+ T cells activated in vitro.