Protein Kinase B Regulates T Lymphocyte Survival, Nuclear Factor κb Activation, and Bcl-XL Levels in Vivo

Abstract

The serine/threonine kinase protein kinase B (PKB)/Akt mediates cell survival in a variety of systems. We have generated transgenic mice expressing a constitutively active form of PKB (gag-PKB) to examine the effects of PKB activity on T lymphocyte survival. Thymocytes and mature T cells overexpressing gag-PKB displayed increased active PKB, enhanced viability in culture, and resistance to a variety of apoptotic stimuli. PKB activity prolonged the survival of CD4+CD8+ double positive (DP) thymocytes in fetal thymic organ culture, but was unable to prevent antigen-induced clonal deletion of thymocytes expressing the major histocompatibility complex class I–restricted P14 T cell receptor (TCR). In mature T lymphocytes, PKB can be activated in response to TCR stimulation, and peptide-antigen–specific proliferation is enhanced in T cells expressing the gag-PKB transgene. Both thymocytes and T cells overexpressing gag-PKB displayed elevated levels of the antiapoptotic molecule Bcl-XL. In addition, the activation of peripheral T cells led to enhanced nuclear factor (NF)-κB activation via accelerated degradation of the NF-κB inhibitory protein IκBα. Our data highlight a physiological role for PKB in promoting survival of DP thymocytes and mature T cells, and provide evidence for the direct association of three major survival molecules (PKB, Bcl-XL, and NF-κB) in vivo in T lymphocytes.

Activated Akt promotes increased resting T cell size, CD28‐independent T cell growth, and development of autoimmunity and lymphoma

“…mAkttransgenic T cells described here were less resistant to death than those described by Jones et al [41] to a variety of stimulations, including dexamethasone (data not shown) and death-by-neglect. A possible explanation for this difference is the lack of detectable Bcl-xL induction in transgenic thymocytes described here (data not shown) compared those of Jones et al [41]. Overall, the findings described here share the late developmental effects of constitutive Akt activation in T cells previously described.…”

“…In addition, T cell-specific Akt-transgenic mice have been previously described to accumulate CD4 T cells and B cells with age and to develop autoimmunity [40]. mAkttransgenic T cells described here were less resistant to death than those described by Jones et al [41] to a variety of stimulations, including dexamethasone (data not shown) and death-by-neglect. A possible explanation for this difference is the lack of detectable Bcl-xL induction in transgenic thymocytes described here (data not shown) compared those of Jones et al [41].…”

Role of the pro-survival molecule Bfl-1 in melanoma

“…Perhaps surprisingly, both Akt1 -/-and Akt2 -/-mice were viable, and even the double knockout Akt1/2 -/-mice developed normally through embryogenesis, suggesting the three isoforms can substitute for each other in cellular processes, at least during development 217 . In transgenic mice expressing constitutively activated Akt, increased resistance to apoptosis and increased tumour formation were observed 218 . 219 .…”

Akt inhibition upregulates FasL, downregulates c-FLIPs and induces caspase-8-dependent cell death in Jurkat T lymphocytes

“…[1][2][3][4] Akt is activated through the direct binding of phosphatidylinositol (3,4,5)-triphosphate (PIP 3 ), a lipid second messenger generated by phosphatidylinositol-3-kinase (PI3K). 5,6 PIP 3 generated by the action of PI3K binds Akt via the pleckstrin homology (PH) domain of Akt, followed by 3-phosphoinositide-dependent protein kinase 1 (PDK1)-mediated phosphorylation at Thr-308 and Ser-473.…”