FOXO3 is differentially required for CD8⁺ T-cell death during tolerance versus immunity

Peripheral tolerance mechanisms limit autoimmunity by constitutively eliminating self-reactive CD8⁺ T cells from the periphery in a process called deletion. Previous work has demonstrated that this deletion process is mediated by BIM-dependent apoptotic death due to transcriptional induction of the Bim gene. Currently, the transcriptional pathways responsible for Bim induction during peripheral deletion remain unclear. We speculated that the transcriptional regulator FOXO3 may induce BIM-dependent death during peripheral deletion, as it has been implicated in Bim induction and cell death during effector CD8⁺ T-cell differentiation. Despite observing less Akt-dependent inactivation of FOXO transcription factors in tolerised cells relative to effector cells, we demonstrate that FOXO3-deficient CD8⁺ T cells induce Bim and die normally during peripheral deletion. These data thus demonstrate that BIM-dependent death during CD8⁺ T-cell deletion is FOXO3 independent. Furthermore, these data provide the first evidence that the pathways responsible for Bim induction and cell death during effector differentiation versus tolerance of CD8⁺ T cells are molecularly distinct.