biostudies-literatureShan QBLRD VAU.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious DiseasesNIAID NIH HHSU.S. Department of Veterans Affairs1222-1235https://www.ebi.ac.uk/biostudies/studies/S-EPMC9579964biostudies-literatureUnknown23(8)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 cNature immunologyTcf1-CTCF cooperativity shapes genomic architecture to promote CD8⁺ T cell homeostasis.PMC9579964R01 AI121080BX005771R01 AI112579I01 BX005771AI112579AI121080AI139874R01 AI139874Yuan SLi XXue HHLiu JPeng WShan QChen XZhu SfalseTcf1-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 c2022-01-01T00:00:00Z2022 Aug2026-05-10T06:51:50.137Z2025-02-19T03:25:54.521ZS-EPMC95799643588293610.1038/s41590-022-01263-6