Graded Foxo1 activity in Treg cells differentiates tumour immunity from spontaneous autoimmunity

The transcription factor Foxo1 is shown to be involved in the determination of distinct subsets of regulatory T (Treg) cells, and the differentiation of activated phenotype Treg cells is associated with the repression of the Foxo1-dependent transcriptional program; constitutively active Foxo1 expression triggers depletion of activated Treg cells in peripheral tissues and leads to CD8 T-cell-mediated autoimmunity and anti-tumour immunity. Ming Li and colleagues provide evidence that the transcription factor Foxo1 plays a role in the determination of distinct subsets of regulatory T (Treg) cells, and show that differentiation of activated phenotype Treg cells is associated with repression of the Foxo1-dependent transcriptional program. Constitutively active Foxo1 expression triggers depletion of Treg cells in peripheral tissues and leads to lethal CD8 T-cell-mediated autoimmunity. Tumour-infiltrating Treg cells may be more sensitive to Foxo1 gain of function. Regulatory T (Treg) cells expressing the transcription factor Foxp3 have a pivotal role in maintaining immunological self-tolerance1,2,3,4,5; yet, excessive Treg cell activities suppress anti-tumour immune responses6,7,8. Compared to the resting Treg (rTreg) cell phenotype in secondary lymphoid organs, Treg cells in non-lymphoid tissues exhibit an activated Treg (aTreg) cell phenotype9,10,11. However, the function of aTreg cells and whether their generation can be manipulated are largely unexplored. Here we show that the transcription factor Foxo1, previously demonstrated to promote Treg cell suppression of lymphoproliferative diseases12,13, has an unexpected function in inhibiting aTreg-cell-mediated immune tolerance in mice. We find that aTreg cells turned over at a slower rate than rTreg cells, but were not locally maintained in tissues. aTreg cell differentiation was associated with repression of Foxo1-dependent gene transcription, concomitant with reduced Foxo1 expression, cytoplasmic localization and enhanced phosphorylation at the Akt sites. Treg-cell-specific expression of an Akt-insensitive Foxo1 mutant prevented downregulation of lymphoid organ homing molecules, and impeded Treg cell homing to non-lymphoid organs, causing CD8+ T-cell-mediated autoimmune diseases. Compared to Treg cells from healthy tissues, tumour-infiltrating Treg cells downregulated Foxo1 target genes more substantially. Expression of the Foxo1 mutant at a lower dose was sufficient to deplete tumour-associated Treg cells, activate effector CD8+ T cells, and inhibit tumour growth without inflicting autoimmunity. Thus, Foxo1 inactivation is essential for the migration of aTreg cells that have a crucial function in suppressing CD8+ T-cell responses; and the Foxo signalling pathway in Treg cells can be titrated to break tumour immune tolerance preferentially.