Evidence for a role for notch signaling in the cytokine-dependent survival of activated T cells.
Peripheral T cell homeostasis results from a balance between factors promoting survival and those that trigger deletion of Ag-reactive cells. The cytokine IL-2 promotes T cell survival whereas reactive oxygen species (ROS) sensitize T cells to apoptosis. Two pathways of activated T cell apoptosis-one triggered by Fas ligand and the other by cytokine deprivation-depend on ROS, with the latter also regulated by members of the Bcl-2 family. Notch family proteins regulate several cell-fate decisions in metazoans. Ectopic expression of the Notch1 intracellular domain (NICD) in T cells inhibits Fas-induced apoptosis. The underlying mechanism is not known and the role, if any, of Notch in regulating apoptosis triggered by cytokine deprivation or neglect has not been examined. In this study, we use a Notch1/Fc chimera; a blocking Ab to Notch1 and chemical inhibitors of gamma-secretase to investigate the role of Notch signaling in activated T cells of murine origin. We show that perturbing Notch signaling in activated CD4+/CD8+ T cells maintained in IL-2 results in the accumulation of ROS, reduced Akt/protein kinase B activity, and expression of the antiapoptotic protein Bcl-xL, culminating in apoptosis. A broad-spectrum redox scavenger inhibits apoptosis but T cells expressing mutant Fas ligand are sensitive to apoptosis. Activated T cells isolated on the basis of Notch expression (Notch+) are enriched for Bcl-xL expression and demonstrate reduced susceptibility to apoptosis triggered by neglect or oxidative stress. Furthermore, enforced expression of NICD protects activated T cells from apoptosis triggered by cytokine deprivation. Taken together, these data implicate Notch1 signaling in the cytokine-dependent survival of activated T cells.
Bheeshmachar
Geetha
G
National Centre for Biological Sciences, Bangalore, Karnataka, India.
Purushotaman
Divya
D
Sade
Hadassah
H
Gunasekharan
Vigneshkumar
V
Rangarajan
Annapoorni
A
Sarin
Apurva
A
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D016207:Cytokines / Q000494:pharmacology; D006706:Homeostasis; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007376:Interleukin-2 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D051881:Receptor, Notch1 / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology*
D016207:Cytokines; D007141:Immunoglobulin Fc Fragments; D007376:Interleukin-2; D051881:Receptor, Notch1; D011993:Recombinant Fusion Proteins