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

Department of Biological Sciences, National Research Laboratory of Molecular Genetics, Biomedical Research Center, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
PLoS ONE (Impact Factor: 3.53). 11/2009; 4(11):e8011. DOI: 10.1371/journal.pone.0008011
Source: PubMed

ABSTRACT 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.
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 gamma-irradiation and paraquat-induced oxidative stresses, whereas those from Mst1 Tg mice were resistant.
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.


Available from: Sean Bong Lee, Jun 05, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background As individual naïve CD4 T lymphocytes circulate in the body after emerging from the thymus, they are likely to have individually varying microenvironmental interactions even in the absence of stimulation via specific target recognition. It is not clear if these interactions result in alterations in their activation, survival and effector programming. Naïve CD4 T cells show unimodal distribution for many phenotypic properties, suggesting that the variation is caused by intrinsic stochasticity, although underlying variation due to subsets created by different histories of microenvironmental interactions remains possible. To explore this possibility, we began examining the phenotype and functionality of naïve CD4 T cells differing in a basic unimodally distributed property, the CD4 levels, as well as the causal origin of these differences.ResultsWe examined separated CD4hi and CD4lo subsets of mouse naïve CD4 cells. CD4lo cells were smaller with higher CD5 levels and lower levels of the dual-specific phosphatase (DUSP)6-suppressing micro-RNA miR181a, and responded poorly with more Th2-skewed outcomes. Human naïve CD4lo and CD4hi cells showed similar differences. Naïve CD4lo and CD4hi subsets of thymic single-positive CD4 T cells did not show differences whereas peripheral naïve CD4lo and CD4hi subsets of T cell receptor (TCR)-transgenic T cells did. Adoptive transfer-mediated parking of naïve CD4 cells in vivo lowered CD4 levels, increased CD5 and reactive oxygen species (ROS) levels and induced hyporesponsiveness in them, dependent at least in part on availability of major histocompatibility complex class II (MHCII) molecules. ROS scavenging or DUSP inhibition ameliorated hyporesponsiveness. Naïve CD4 cells from aged mice showed lower CD4 levels and cell sizes, higher CD5 levels, and hyporesponsiveness and Th2-skewing reversed by DUSP inhibition.Conclusions Our data show that, underlying a unimodally distributed property, the CD4 level, there are subsets of naïve CD4 cells that vary in the time spent in the periphery receiving MHCII-mediated signals and show resultant alteration of phenotype and functionality via ROS and DUSP activity. Our findings also suggest the feasibility of potential pharmacological interventions for improved CD4 T cell responses during vaccination of the elderly via either anti-oxidant or DUSP inhibitor small molecules.
    BMC Biology 12/2014; 12(1):106. DOI:10.1186/s12915-014-0106-0 · 7.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The canonical Hippo/Mst pathway, originally discovered in Drosophila, is famous for its function in promoting apoptosis, inhibiting cell proliferation and tumorigenesis, and regulating tissue regeneration. However, emerging evidences show that multiple non-canonical Hippo signaling pathways are also implicated in the regulation of various other biological processes. Recent studies have revealed that Mst1/2, the core kinases of Hippo/Mst pathway are required for T cell development, function, survival, trafficking, homing, and also involved in regulation of autoimmunity. In this review, we discuss the roles of non-canonical Hippo/Mst signaling pathways in lymphocyte development and functions. © The Author 2014. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.
    Acta Biochimica et Biophysica Sinica 12/2014; DOI:10.1093/abbs/gmu112 · 2.09 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Engagement of the TCR/CD3 complex triggers a cascade of events that result in T lymphocyte activation and promote positive and negative selection of thymocytes, T lymphocyte migration and effector functions, development and activation of regulatory T cells. Gene mutations that abrogate early TCR signaling are associated with profound abnormalities of T lymphocyte development and function both in humans and in mice, causing susceptibility to severe infections since early in life. In recent years, a growing number of genetic defects have been discovered that reduce, but do not completely abrogate proximal TCR signaling. These defects result in complex phenotypic manifestations that are not limited to immunodeficiency, but also include immune dysregulation. The identification of these conditions may also prompt development of novel therapeutic strategies for autoimmune disorders.
    Current Opinion in Immunology 12/2014; 31:97–101. DOI:10.1016/j.coi.2014.10.003 · 7.87 Impact Factor