FOXO1 levels in Treg cells balance antitumor immunity with increased autoimmunity.

  • Major finding: FOXO1 levels in Treg cells balance antitumor immunity with increased autoimmunity.

  • Mechanism: Activation of AKT and inhibition of FOXO1 expression and localization is essential for aTreg homeostasis.

  • Impact: Depletion of aTreg cells by FOXO1 may promote the antitumor immune response.

Regulatory T cells (Treg) expressing forkhead box O1 (FOXO1) mediate the response to self-antigens, preventing autoimmunity. However, excess Treg activity can disrupt antitumor immunity, promoting tumor growth, and tumors with increased Treg infiltration are associated with a poorer prognosis. FOXO1 activity is required for Treg function, and enhances Treg suppression of lymphoproliferative diseases, but its role in activated Treg (aTreg) and resting Treg (rTreg) subsets has not been determined. To address this, Luo and colleagues performed gene expression profiling of aTregs and rTregs. The aTregs preferentially expressed FOXO1-downregulated genes, while the rTregs preferentially expressed FOXO1-upregulated genes. AKT phosphorylation prevents FOXO1 nuclear localization, and in aTregs AKT activation resulted in FOXO1 translocation to the cytoplasm and repression of FOXO1. Conversely, rTreg cells expressed higher levels of FOXO1, which was predominantly localized to the nucleus. In vivo, expression of a constitutively active form of FOXO1 (CA) that is insensitive to inhibition by AKT reduced the number of aTreg cells, without affecting rTreg cells, and resulted in CD8+ T cell–mediated inflammation and tissue destruction, indicating that aTregs are essential in suppressing autoimmunity. In a mammary tumor model (PyMT), CA reduced the number of tumor-infiltrating Tregs and suppressed tumor growth. Depletion of CD8+ T cells prevented the tumor suppression, indicating that the antitumor effect is mediated by CD8+ T cells. Altogether, these results suggest that repression of FOXO1 activity is essential for the differentiation of aTregs from rTregs, and excessive FOXO activity promotes loss of aTregs allowing for CD8+ effector T-cell activity. FOXO1 simultaneously inhibits tumor growth and promotes spontaneous autoimmunity, but the high sensitivity of tumor cells to FOXO1-mediated Treg depletion may allow for titration of FOXO1 levels to suppress tumors without inducing autoimmunity.

Luo CT, Liao W, Dadi S, Toure A, Li MO. Graded Foxo1 activity in Treg cells differentiates tumour immunity from spontaneous autoimmunity. Nature 2016;529:532–6.

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