The Interplay of Transcription and Genome Topology Programs T Cell Development and Differentiation

T cells are essential for mounting defense against vari-ous pathogens and malignantly transformed cells. Thy-mic development and peripheral T cell differentiation are highly orchestrated biological processes that require precise gene regulation. Higher-order genome organi-zation on multiple scales, in the form of chromatin loops, topologically associating domains and compart-ments, provides pivotal control of T cell gene expression. CTCF and the cohesin machinery are ubiquitously expressed architectural proteins responsible for establish-ing chromatin structures. Recent studies indicate that transcription factors, such as T lineage -defining Tcf1 and TCR-induced Batf, may have intrinsic ability and/or engage CTCF to shape chromatin architecture. In this article, we summarize current knowledge on the dynamic changes in genome topology that underlie normal or leu-kemic T cell development, CD41 helper T cell differen-tiation, and CD81 cytotoxic T cell functions. The knowledge lays a solid foundation for elucidating the causative link of spatial chromatin configuration to tran-scriptional and functional output in T cells. The Journal ofImmunology, 2022, 209: 2269-2278.

Automated summary

T cells play a crucial role in defending against pathogens and malignant cells, and their development and differentiation rely on precise gene regulation. Higher-order genome organization, including chromatin loops and topologically associating domains, controls T cell gene expression. Recent studies have highlighted the role of transcription factors and CTCF in shaping chromatin architecture. This article summarizes current knowledge on the dynamic changes in genome topology during T cell development and function, providing a foundation for understanding the causal link between chromatin configuration and T cell transcriptional and functional outputs.