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Evidence for a Role for Notch Signaling in the Cytokine-Dependent Survival of Activated T Cells¹

Geetha Bheeshmachar^2,*, Divya Purushotaman^2,*, Hadassah Sade^*, Vigneshkumar Gunasekharan, Annapoorni Rangarajan and Apurva Sarin^3,*

^* National Centre for Biological Sciences, Bangalore, Karnataka, India; and Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, Karnataka, India

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 -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-x_L, 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-x_L 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a Senior Research Fellowship in Biomedical Sciences from the Wellcome Trust, U.K. (to A.S.). P.D. was funded by a Junior Research Fellowship from the Council of Scientific and Industrial Research, India.

² B.G. and P.D. contributed equally.

³ Address correspondence and reprint requests to Dr. Apurva Sarin, National Centre for Biological Sciences, Bellary Road, Bangalore 560065, Karnataka, India. E-mail address: sarina{at}ncbs.res.in

⁴ Abbreviations used in this paper: NIC, Notch1 intracellular; NICD, NIC domain; PKB, protein kinase B; AICD, activation-induced cell death; A-NID, activated T cell neglect-induced death; ROS, reactive oxygen species; TCB, T cell blast; MnTBAP, Mn(III)tetrakis(4-benzoic acid) porphyrin chloride; DHE, dihydroethidium; Notch^L, Notch-low; GSI, -secretase inhibitor; NCT, Notch C terminus; _c, common -chain.

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