Tcf1–CTCF cooperativity shapes genomic architecture to promote CD8 + T cell homeostasis

CD8 + T cell homeostasis is maintained by the cytokines IL-7 and IL-15. Here we show that transcription factors Tcf1 and Lef1 were intrinsically required for homeostatic proliferation of CD8 + T cells. Multiomics analyses showed that Tcf1 recruited the genome organizer CTCF and that homeostatic cytokines induced Tcf1-dependent CTCF redistribution in the CD8 + T cell genome. Hi-C coupled with network analyses indicated that Tcf1 and CTCF acted cooperatively to promote chromatin interactions and form highly connected, dynamic interaction hubs in CD8 + T cells before and after cytokine stimulation. Ablating CTCF phenocopied the proliferative defects caused by Tcf1 and Lef1 deficiency. Tcf1 and CTCF controlled a similar set of genes that regulated cell cycle progression and promoted CD8 + T cell homeostatic proliferation in vivo. These findings identified CTCF as a Tcf1 cofactor and uncovered an intricate interplay between Tcf1 and CTCF that modulates the genomic architecture of CD8 + T cells to preserve homeostasis.