Notch and the Survival of Regulatory T Cells: Location Is Everything!

Signaling through the T cell receptor induces T lymphocytes to divide, differentiate, and perform numerous effector functions. Once activated, effector T cells are exquisitely sensitive to changes in available cytokines, particularly the survival cytokine interleukin-2 (IL-2). Removal of IL-2 rapidly initiates apoptosis in response to cytokine withdrawal. In contrast to effector T cells, regulatory T cells (T-regs) are resistant to apoptosis induced by cytokine withdrawal. A study exploring the differences between these two T cell subsets reveals a role for Notch1 in protecting T-regs from apoptosis. Protection from apoptosis induced by cytokine withdrawal correlated with Notch1 localization in the cytosol of T-regs and its association with phosphatidylinositol 3-kinase and Rictor, a component of the mammalian target of rapamycin complex. Notch1 localization in the nucleus in effector T cells, on the other hand, was correlated with susceptibility to apoptosis induced by cytokine withdrawal. This study highlights how Notch1 can deliver opposing signals in different cellular contexts and suggests that localization of Notch1 can have a substantial influence on life-and-death decisions in T lymphocytes.