biostudies-literatureMurphy MKNIAID NIH HHS2472-2488.e9https://www.ebi.ac.uk/biostudies/studies/S-EPMC12717841biostudies-literatureUnknown58(10)During differentiation of CD8⁺ T cells, the transcription factors TCF-1 and Blimp1 control progenitor and terminally differentiated states, respectively. Here, we examined the hierarchy and functional consequences of cross-regulation between these factors. We identified two Blimp1-bound cis-regulatory elements, Tcf7^+22kb and Tcf7^+17kb, that enforced Tcf7 silencing in a context-specific manner during both acute and chronic responses. Deletion of these elements decoupled Tcf7 repression from effector differentiation but did not rewire effector T cells to a memory state or prevent the acquisition of phenotypic hallmarks of exhaustion. However, combined ablation of Prdm1 and Tcf7 preserved a memory surface phenotype despite defects in secondary expansion. Thus, the anti-proliferative and pro-differentiative effects of Blimp1 in effector or exhausted CD8⁺ T cells represent mechanistically distinct modules, wherein repression of Tcf7 limits proliferative capacity but not memory or progenitor specification.ImmunityThe transcriptional repressor BLIMP1 enforces TCF-1-dependent and -independent restriction of the memory fate of CD8<sup>+</sup> T cells.PMC12717841T32 AI007163F31 AI174696R01 AI134035R01 AI170926R01 AI130152R01 AI176664Deffenbaugh JLEgawa TColonna MChen AYHsiung SMurphy MKPai JOltz EMDaniel BGhoneim HESatpathy ATYousif ARaju SMcCullen MWang ZfalseThe transcriptional repressor BLIMP1 enforces TCF-1-dependent and -independent restriction of the memory fate of CD8<sup>+</sup> T cells.During differentiation of CD8⁺ T cells, the transcription factors TCF-1 and Blimp1 control progenitor and terminally differentiated states, respectively. Here, we examined the hierarchy and functional consequences of cross-regulation between these factors. We identified two Blimp1-bound cis-regulatory elements, Tcf7^+22kb and Tcf7^+17kb, that enforced Tcf7 silencing in a context-specific manner during both acute and chronic responses. Deletion of these elements decoupled Tcf7 repression from effector differentiation but did not rewire effector T cells to a memory state or prevent the acquisition of phenotypic hallmarks of exhaustion. However, combined ablation of Prdm1 and Tcf7 preserved a memory surface phenotype despite defects in secondary expansion. Thus, the anti-proliferative and pro-differentiative effects of Blimp1 in effector or exhausted CD8⁺ T cells represent mechanistically distinct modules, wherein repression of Tcf7 limits proliferative capacity but not memory or progenitor specification.2025-01-01T00:00:00Z2025 Oct2026-06-06T04:43:57.23Z2026-05-25T03:12:13.574ZS-EPMC127178414104341410.1016/j.immuni.2025.09.008