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

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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 theBimgene. Currently, the transcriptional pathways responsible forBiminduction 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 inBiminduction 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 induceBimand 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 forBiminduction and cell death during effector differentiation versus tolerance of CD8+ T cells are molecularly distinct.

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