Active maintenance of CD8+ T cell naivety through regulation of global genome architecture

• Published in: Cell reports (Cambridge) Vol. 42; no. 10; p. 113301
• Main Authors: Russ, Brendan E., Barugahare, Adele, Dakle, Pushkar, Tsyganov, Kirril, Quon, Sara, Yu, Bingfei, Li, Jasmine, Lee, Jason K.C., Olshansky, Moshe, He, Zhaohren, Harrison, Paul F., See, Michael, Nussing, Simone, Morey, Alison E., Udupa, Vibha A., Bennett, Taylah J., Kallies, Axel, Murre, Cornelis, Collas, Phillipe, Powell, David, Goldrath, Ananda W., Turner, Stephen J.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 31-10-2023; Cell Press; Elsevier
• Subjects: CD8+ T cell; chromatin; CP: Immunology; CP: Molecular biology; T cell memory; CP: Immunology; CP: Molecular biology; chromatin; CD8+ T cell; T cell memory
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113301

The differentiation of naive CD8+ T lymphocytes into cytotoxic effector and memory CTL results in large-scale changes in transcriptional and phenotypic profiles. Little is known about how large-scale changes in genome organization underpin these transcriptional programs. We use Hi-C to map changes in the spatial organization of long-range genome contacts within naive, effector, and memory virus-specific CD8+ T cells. We observe that the architecture of the naive CD8+ T cell genome is distinct from effector and memory genome configurations, with extensive changes within discrete functional chromatin domains associated with effector/memory differentiation. Deletion of BACH2, or to a lesser extent, reducing SATB1 DNA binding, within naive CD8+ T cells results in a chromatin architecture more reminiscent of effector/memory states. This suggests that key transcription factors within naive CD8+ T cells act to restrain T cell differentiation by actively enforcing a unique naive chromatin state.
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•CD8+ T cell differentiation states are underscored by distinct chromatin looping architectures•Chromatin loops connect CD8+ T cell subset-specific enhancers, transcription factors and genes•Effector and memory CTLs have similar genome architectures, explaining rapid memory recall•BACH2, and to a lesser extent, SATB1, enforce a naive CD8+ T cell loop architecture
Russ et al. use Hi-C to map chromatin architecture dynamics during virus-specific CD8+ T cell differentiation. They demonstrate that key transcription factors preserve naivety by enforcing a naive chromatin state, and that effector and memory states are largely similar, providing a molecular explanation for rapid memory T cell function.