The PTEN stabilizer

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Forkhead box P3-positive (FOXP3⁺) regulatory T (T_Reg) cells maintain immune tolerance and thus, defining the mechanisms that control T_Reg cell function and stability is crucial for understanding how the immune system is regulated. Previous studies have implicated the phosphatase PTEN, which is the main negative regulator of phosphoinositide 3-kinase (PI3K), in T_Reg cell activation. Now, two studies published in Nature Immunology show that PTEN, through the regulation of PI3K and mammalian target of rapamycin (mTOR) complex 2 (mTORC2), is crucial for maintaining T_Reg cell homeostasis, function and stability.

PTEN signalling in T_Reg cells suppresses the spontaneous development of a lympho-proliferative disease

Using similar techniques, both groups generated mice in which T_Reg cells specifically lacked Pten (Pten^fl/flFoxp3-Cre mice). Over time, these mice developed an autoimmune and lymphoproliferative disease with renal pathology. Further analysis of these mice showed an accumulation of germinal centre B cells, high levels of serum autoantibodies and high number of T cells with an activated or memory phenotype. T cells from these mice expressed high levels of interferon-γ (IFNγ) and CXC-chemokine receptor 3, which are both signatures of T helper 1 (T_H1) cells. In addition, high numbers of follicular helper T cells (T_FH cells) were observed in Pten^fl/flFoxp3-Cre mice compared with control mice. Shrestha et al. showed that the increased T_FH cell, germinal centre and autoimmune responses were dependent on the increased production of IFNγ in Pten^fl/flFoxp3-Cre mice. These data suggest that PTEN signalling in T_Reg cells suppresses the spontaneous development of a lymphoproliferative disease involving B cells, T_H1 cells and T_FH cells.

Surprisingly, given the loss of immune tolerance in these mice, high numbers of FOXP3⁺ T_Reg cells, in particular FOXP3⁺CD25⁻ T_Reg cells, were observed in Pten^fl/flFoxp3-Cre mice. Huynh et al. provided data to suggest that PTEN-deficient T_Reg cells might be pathogenic in vivo. Using a lineage-tracing system, both groups found that in addition to a loss of CD25 expression, PTEN-deficient T_Reg cells lost expression of FOXP3 over time and, as shown by Shrestha et al., these 'ex-T_Reg cells' upregulated the expression of molecules characteristic of T_H1 cells and T_FH cells. These data indicate that PTEN maintains T_Reg cell stability.

T_Reg cells from Pten^fl/flFoxp3-Cre mice were shown by both groups to have increased glycolytic metabolism compared with control T_Reg cells, which might disrupt T_Reg cell stability and homeostasis. Loss of PTEN in T_Reg cells also resulted in increased activation of mTORC2 (but not mTORC1) compared with control cells. Abrogation of mTORC2 activity in PTEN-deficient T_Reg cells either through deletion of the mTORC2 component Rictor (Shrestha et al.) or through inhibition of AKT (Huynh et al.), which is downstream of mTORC2, restored CD25 expression. As shown by Shrestha et al., abrogation of mTORC2 activity also blocked the spontaneous development of T_H1 cells, T_FH cells and germinal centre B cells, as well as renal pathology, in Pten^fl/flFoxp3-Cre mice. Inhibition of PI3K, which is upstream of mTORC2, also prevented the loss of CD25 and FOXP3 in PTEN-deficient T_Reg cells in vitro (Huynh et al.).

Thus, the control of PI3K and mTORC2 activity by PTEN maintains T_Reg cell lineage stability, T_Reg cell-mediated control of effector responses and thus immune homeostasis.