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Background  The Ste-20 family kinase Hippo restricts cell proliferation and promotes apoptosis for proper organ development in  Drosophila . In  C. elegans , Hippo homolog also regulates longevity. The mammalian Ste20-like protein kinase, Mst1, plays a role in apoptosis induced by various types of apoptotic stress. Mst1 also regulates peripheral naïve T cell trafficking and proliferation in mice. However, its functions in mammals are not fully understood.    Methodology/Principal Findings  Here, we report that the Mst1-FoxO signaling pathway plays a crucial role in survival, but not apoptosis, of naïve T cells. In  Mst1 −/−   mice, peripheral T cells showed impaired FoxO1/3 activation and decreased FoxO protein levels. Consistently, the FoxO targets, Sod2 and catalase, were significantly down-regulated in  Mst1 −/−   T cells, thereby resulting in elevated levels of intracellular reactive oxygen species (ROS) and induction of apoptosis. Expression of constitutively active FoxO3a restored  Mst1 −/−   T cell survival. Crossing Mst1 transgenic mice ( Mst1  Tg) with  Mst1 −/−   mice reduced ROS levels and restored normal numbers of peripheral naïve T cells in  Mst1  Tg; Mst1 −/−   progeny. Interestingly, peripheral T cells from  Mst1 −/−   mice were hypersensitive to γ-irradiation and paraquat-induced oxidative stresses, whereas those from  Mst1  Tg mice were resistant.    Conclusions/Significance  These data support the hypothesis that tolerance to increased levels of intracellular ROS provided by the Mst1-FoxOs signaling pathway is crucial for the maintenance of naïve T cell homeostasis in the periphery.

Mst1-FoxO Signaling Protects Naïve T Lymphocytes from Cellular Oxidative Stress in Mice