The transcriptional repressor BLIMP1 enforces TCF-1-dependent and -independent restriction of the memory fate of CD8+ 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.