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Division of Cellular Immunology, MRC National Institute for Medical Research, London NW7 1AA, United Kingdom; the Division of Molecular Genetics, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; and the || Cancer Biology and Molecular Haematology Units, Camelia Botnar Laboratories, Institute of Child Health, London WC1N 1EH, United Kingdom
Bad is a distant relative of Bcl-2 and acts to promote cell death. Here, we show that Bad expression levels are greatly increased in thymocytes during apoptosis. We generated bad transgenic mice to study the action of upregulated Bad expression on T cell apoptosis. The T cells from these mice are highly sensitive to apoptotic stimuli, including anti-CD95. The numbers of T cells are greatly depleted and the processes of T cell development and selection are perturbed. We show that the proapoptotic function of Bad in primary T cells is regulated by Akt kinase and that Bad overexpression enhances both cell cycle progression and interleukin 2 production after T cell activation. These data suggest that Bad can act as a key regulator of T cell apoptosis and that this is a consequence of its upregulation after exposure to death stimuli.
Key Words: Bad • apoptosis • selection • cell cycle • Akt
This research was funded by the Medical Research Council. G. Gil-Gómez was partially funded by a fellowship from the Spanish Government's Ministerio de Educacion y Cultura and by European Commission contract CHRX-CT94-0584. O. Williams was the recipient of a Leukemia Research Fund fellowship.
1 Abbreviations used in this paper: BH, Bcl-2 homology; HA, hemagglutinin; LCR, locus control region; PI-3-K, phosphatidylinositide-3-kinase; RAG-1, recombination activation gene 1.
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